<p>Perianal fistulizing Crohn’s disease affects a third of patients with Crohn’s disease and represents one of the most challenging complications to manage. This severe phenotype is characterized by aggressive disease behavior, high recurrence rates, frequent hospitalizations and surgical interventions, and profound impairment of quality of life, particularly affecting social and sexual function. The complex pathophysiology involves genetic susceptibility, immune dysregulation with elevated inflammatory cytokines, epithelial-to-mesenchymal transition, myofibroblast activation, and impaired wound healing mechanisms. Despite advances in anti-inflammatory and immunomodulatory therapies, current medical and surgical approaches achieve long-term fistula healing in only approximately 50% of patients. More than 90% of patients undergo multiple operative interventions, often with limited efficacy and risk of fecal incontinence. Anti-tumor necrosis factor agents, particularly infliximab, remain the cornerstone of medical therapy, yet more than 50% of patients lose response over time. Combination approaches with setons and biologics improve outcomes but remain suboptimal for many patients.These persistent limitations have prompted increasing interest in regenerative strategies aimed at restoring tissue integrity and enhancing local healing mechanisms. Mesenchymal stem cell therapy, particularly adipose-derived stem cells, has emerged as a promising approach, with clinical trials demonstrating complete fistula healing in the majority of cases and a favorable safety profile, but there are limitations with logistics of cell handling and negative late phase pivotal trials. This review evaluates the current landscape of novel regenerative therapies for perianal fistulizing Crohn’s disease, including mesenchymal stem cell preparations, extracellular vesicle-based approaches, and adjunctive techniques.</p>