Synovium-derived mesenchymal stromal cell (Sy-MSC) is a newer member of the mesenchymal stromal cell families. The first successful demonstration of the mesenchymal stromal cell from the human synovial membrane was done in 2001 and since then its potential role for musculoskeletal regeneration has been keenly documented. The regenerative effects of Sy-MSCs are through paracrine signaling, direct cell–cell interactions, and extracellular vehicles. Sy-MSCs possess superior chondrogenicity than other sources of mesenchymal stromal cells. This article aims to outline the advancement of synovium-derived mesenchymal stromal cells along with a specific insight into the application for managing osteoarthritis knee.