Perianal Crohn's disease is a morbid and disabling condition, notoriously difficult to successfully treat with conventional medical and surgical therapies. Mesenchymal stem cells (MSCs) are an emerging novel therapy for perianal Crohn's disease.Over 300 patients with perianal Crohn's disease have now been treated with MSCs in the context of clinical trials. All trials have demonstrated safety, and efficacy superior to conventional therapy with biologics and surgical intervention. This was consistent despite the heterogeneity in study protocols including variability in cell dosing, mode of delivery, repeat dosing, and allogeneic versus autologous donors. Sustained healing to 1 year has also been demonstrated in a recent extension of the largest phase III study confirming superior efficacy of MSCs to placebo at 1-year follow-up. However, several outstanding questions regarding the use of MSCs for perianal Crohn's disease remain, which, if answered, could enhance MSCs' treatment efficacy. These include defining the optimal MSC donor, optimal MSC source (e.g., bone marrow versus adipose tissue), investigating a potential alloimmune response following allogeneic cellular delivery, and determining the optimal mode for MSC delivery. In addition to these unanswered questions, significant challenges in the required infrastructure and cost required for cell-based therapies may drive future research toward identifying novel acellular therapies.Novel regenerative therapies offer promising new treatment options for perianal Crohn's disease, without the risk of opportunistic infection seen with biologics and incontinence with surgical techniques. Future research will help define the optimal MSC product and treatment protocol, and may even expand our horizon of regenerative medicine into acellular therapy as well as cell-based therapies.