Mesenchymal stromal cells (MSCs) express a wide range of properties anticipated to be beneficial for treating genetic, mechanical, and age-related degeneration in diseases such as osteoarthritis (OA). Although contemporary conservative management of OA is successful in many patients with mild-moderate OA, it often fails to improve symptoms in many patients who are not a candidate for any surgical management. Further, existing conservative treatment strategies do not prevent the progression of the disease and therefore fail to provide a long-term pain-free life. On the other hand, tremendous progress has been taking place in the exciting field of regenerative medicine involving MSCs (autologous and allogeneic), with promising translation taking place from basic science to the bedside. In this review, we comprehensively discuss the potential role of MSCs in treating OA, both autologous and off-the-shelf, allogeneic stem cells. Further, newer therapies are in the offing to treat OA, such as exosomes and growth factors.