To date, many animal studies have indicated the neuroprotective effects of mesenchymal stem cell (MSC) transplantation in ischemic stroke. Several clinical studies have also revealed the safety, feasibility, and neuroprotective effects in ischemic stroke patients. In this review, we present the main approaches of MSC transplantation in ischemic stroke, the mechanisms of MSC therapy, and the current clinical studies on MSC transplantation in ischemic stroke patients. We also explore the safety of MSC transplantation and conclude that MSC therapy will play an important role in the future treatment of ischemic stroke. The optimal timing, approach, and cell dose in the transplantation are important issues for successful clinical application.