Osteoarthritis (OA) is designated the 11th highest contributor of 291 diseases of global disability and the most common cause of chronic disability in elderly people. OA has a devastating impact on quality of life and represents an enormous socio-economic burden. Currently, OA is incurable, and no approved medications, biological therapy, or procedure prevents the progressive destruction of the osteoarthritic knee joint. All current treatments provide symptomatic relief rather than preventative or regenerative results. There is an urgent and compelling need to find, validate, and test new biological therapeutics. Cell-based therapies involving the delivery of mesenchymal stromal cells (MSCs) to the os-teoarthritic knee joint have emerged as a potential solution to overcome this clinical shortcoming. In this review, we address the clinical evidence, challenges, and recent advances surrounding MSC treatment in knee OA.