diff --git a/federationsender/queue/destinationqueue.go b/federationsender/queue/destinationqueue.go
index ce706768e..e2314ebbe 100644
--- a/federationsender/queue/destinationqueue.go
+++ b/federationsender/queue/destinationqueue.go
@@ -250,6 +250,12 @@ func (oq *destinationQueue) backgroundSend() {
 					oq.cleanPendingEDUs()
 					oq.cleanPendingInvites()
 					return
+				} else {
+					// We haven't been told to give up terminally yet but we still have
+					// PDUs waiting to be sent. By sending a message into the wake chan,
+					// the next loop iteration will try processing these PDUs again,
+					// subject to the backoff.
+					oq.wakeServerCh <- true
 				}
 			} else if transaction {
 				// If we successfully sent the transaction then clear out
diff --git a/federationsender/queue/queue.go b/federationsender/queue/queue.go
index 492d5f553..bc7ec0f93 100644
--- a/federationsender/queue/queue.go
+++ b/federationsender/queue/queue.go
@@ -51,7 +51,7 @@ func NewOutgoingQueues(
 	statistics *types.Statistics,
 	signing *SigningInfo,
 ) *OutgoingQueues {
-	return &OutgoingQueues{
+	queues := &OutgoingQueues{
 		db:         db,
 		rsAPI:      rsAPI,
 		origin:     origin,
@@ -60,6 +60,15 @@ func NewOutgoingQueues(
 		signing:    signing,
 		queues:     map[gomatrixserverlib.ServerName]*destinationQueue{},
 	}
+	// Look up which servers we have pending items for and then rehydrate those queues.
+	if serverNames, err := db.GetPendingServerNames(context.Background()); err == nil {
+		for _, serverName := range serverNames {
+			queues.getQueue(serverName).wakeQueueIfNeeded()
+		}
+	} else {
+		log.WithError(err).Error("Failed to get server names for destination queue hydration")
+	}
+	return queues
 }
 
 // TODO: Move this somewhere useful for other components as we often need to ferry these 3 variables
diff --git a/federationsender/storage/interface.go b/federationsender/storage/interface.go
index 09d74ed7e..4bf36c247 100644
--- a/federationsender/storage/interface.go
+++ b/federationsender/storage/interface.go
@@ -31,4 +31,5 @@ type Database interface {
 	GetNextTransactionPDUs(ctx context.Context, serverName gomatrixserverlib.ServerName, limit int) (gomatrixserverlib.TransactionID, []*gomatrixserverlib.HeaderedEvent, error)
 	CleanTransactionPDUs(ctx context.Context, serverName gomatrixserverlib.ServerName, transactionID gomatrixserverlib.TransactionID) error
 	GetPendingPDUCount(ctx context.Context, serverName gomatrixserverlib.ServerName) (int64, error)
+	GetPendingServerNames(ctx context.Context) ([]gomatrixserverlib.ServerName, error)
 }
diff --git a/federationsender/storage/postgres/queue_pdus_table.go b/federationsender/storage/postgres/queue_pdus_table.go
index bc22825d8..dab6003e9 100644
--- a/federationsender/storage/postgres/queue_pdus_table.go
+++ b/federationsender/storage/postgres/queue_pdus_table.go
@@ -63,6 +63,9 @@ const selectQueuePDUsCountSQL = "" +
 	"SELECT COUNT(*) FROM federationsender_queue_pdus" +
 	" WHERE server_name = $1"
 
+const selectQueueServerNamesSQL = "" +
+	"SELECT DISTINCT server_name FROM federationsender_queue_pdus"
+
 type queuePDUsStatements struct {
 	insertQueuePDUStmt                *sql.Stmt
 	deleteQueueTransactionPDUsStmt    *sql.Stmt
@@ -70,6 +73,7 @@ type queuePDUsStatements struct {
 	selectQueuePDUsByTransactionStmt  *sql.Stmt
 	selectQueueReferenceJSONCountStmt *sql.Stmt
 	selectQueuePDUsCountStmt          *sql.Stmt
+	selectQueueServerNamesStmt        *sql.Stmt
 }
 
 func (s *queuePDUsStatements) prepare(db *sql.DB) (err error) {
@@ -95,6 +99,9 @@ func (s *queuePDUsStatements) prepare(db *sql.DB) (err error) {
 	if s.selectQueuePDUsCountStmt, err = db.Prepare(selectQueuePDUsCountSQL); err != nil {
 		return
 	}
+	if s.selectQueueServerNamesStmt, err = db.Prepare(selectQueueServerNamesSQL); err != nil {
+		return
+	}
 	return
 }
 
@@ -190,3 +197,24 @@ func (s *queuePDUsStatements) selectQueuePDUs(
 
 	return result, rows.Err()
 }
+
+func (s *queuePDUsStatements) selectQueueServerNames(
+	ctx context.Context, txn *sql.Tx,
+) ([]gomatrixserverlib.ServerName, error) {
+	stmt := sqlutil.TxStmt(txn, s.selectQueueServerNamesStmt)
+	rows, err := stmt.QueryContext(ctx)
+	if err != nil {
+		return nil, err
+	}
+	defer internal.CloseAndLogIfError(ctx, rows, "queueFromStmt: rows.close() failed")
+	var result []gomatrixserverlib.ServerName
+	for rows.Next() {
+		var serverName gomatrixserverlib.ServerName
+		if err = rows.Scan(&serverName); err != nil {
+			return nil, err
+		}
+		result = append(result, serverName)
+	}
+
+	return result, rows.Err()
+}
diff --git a/federationsender/storage/postgres/storage.go b/federationsender/storage/postgres/storage.go
index be28c15dc..80686e090 100644
--- a/federationsender/storage/postgres/storage.go
+++ b/federationsender/storage/postgres/storage.go
@@ -264,3 +264,11 @@ func (d *Database) GetPendingPDUCount(
 ) (int64, error) {
 	return d.selectQueuePDUCount(ctx, nil, serverName)
 }
+
+// GetPendingServerNames returns the server names that have PDUs
+// waiting to be sent.
+func (d *Database) GetPendingServerNames(
+	ctx context.Context,
+) ([]gomatrixserverlib.ServerName, error) {
+	return d.selectQueueServerNames(ctx, nil)
+}
diff --git a/federationsender/storage/sqlite3/queue_pdus_table.go b/federationsender/storage/sqlite3/queue_pdus_table.go
index 955ff507d..33eef91ed 100644
--- a/federationsender/storage/sqlite3/queue_pdus_table.go
+++ b/federationsender/storage/sqlite3/queue_pdus_table.go
@@ -64,6 +64,9 @@ const selectQueuePDUsCountSQL = "" +
 	"SELECT COUNT(*) FROM federationsender_queue_pdus" +
 	" WHERE server_name = $1"
 
+const selectQueueServerNamesSQL = "" +
+	"SELECT DISTINCT server_name FROM federationsender_queue_pdus"
+
 type queuePDUsStatements struct {
 	insertQueuePDUStmt                *sql.Stmt
 	deleteQueueTransactionPDUsStmt    *sql.Stmt
@@ -71,6 +74,7 @@ type queuePDUsStatements struct {
 	selectQueuePDUsByTransactionStmt  *sql.Stmt
 	selectQueueReferenceJSONCountStmt *sql.Stmt
 	selectQueuePDUsCountStmt          *sql.Stmt
+	selectQueueServerNamesStmt        *sql.Stmt
 }
 
 func (s *queuePDUsStatements) prepare(db *sql.DB) (err error) {
@@ -96,6 +100,9 @@ func (s *queuePDUsStatements) prepare(db *sql.DB) (err error) {
 	if s.selectQueuePDUsCountStmt, err = db.Prepare(selectQueuePDUsCountSQL); err != nil {
 		return
 	}
+	if s.selectQueueServerNamesStmt, err = db.Prepare(selectQueueServerNamesSQL); err != nil {
+		return
+	}
 	return
 }
 
@@ -188,3 +195,24 @@ func (s *queuePDUsStatements) selectQueuePDUs(
 
 	return result, rows.Err()
 }
+
+func (s *queuePDUsStatements) selectQueueServerNames(
+	ctx context.Context, txn *sql.Tx,
+) ([]gomatrixserverlib.ServerName, error) {
+	stmt := sqlutil.TxStmt(txn, s.selectQueueServerNamesStmt)
+	rows, err := stmt.QueryContext(ctx)
+	if err != nil {
+		return nil, err
+	}
+	defer internal.CloseAndLogIfError(ctx, rows, "queueFromStmt: rows.close() failed")
+	var result []gomatrixserverlib.ServerName
+	for rows.Next() {
+		var serverName gomatrixserverlib.ServerName
+		if err = rows.Scan(&serverName); err != nil {
+			return nil, err
+		}
+		result = append(result, serverName)
+	}
+
+	return result, rows.Err()
+}
diff --git a/federationsender/storage/sqlite3/storage.go b/federationsender/storage/sqlite3/storage.go
index 30ac81bfd..7ba51fb52 100644
--- a/federationsender/storage/sqlite3/storage.go
+++ b/federationsender/storage/sqlite3/storage.go
@@ -270,3 +270,11 @@ func (d *Database) GetPendingPDUCount(
 ) (int64, error) {
 	return d.selectQueuePDUCount(ctx, nil, serverName)
 }
+
+// GetPendingServerNames returns the server names that have PDUs
+// waiting to be sent.
+func (d *Database) GetPendingServerNames(
+	ctx context.Context,
+) ([]gomatrixserverlib.ServerName, error) {
+	return d.selectQueueServerNames(ctx, nil)
+}