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The failure of anti-TNF therapy in the treatment of ano-perineal fistulas in Crohn’s disease is thought to affect around 60% of patients over time. However, before concluding that treatment has failed, certain differential diagnoses must be ruled out, the quality of drainage of the suppuration must be checked, anti-TNF treatment must be optimized, and all available anti-TNF agents must be tested. In the event of proven failure, treatment options depend on the current state of the disease. In the case of active luminal disease, a change of treatment should be considered. In this case, ustekinumab appears to be more effective than vedolizumab. Recent data also support the use of new biotherapies (upadacitinib, risankizumab, and filgotinib) or combination therapy, or even hyperbaric oxygen therapy. In the event of luminal remission, injections of mesenchymal stem cells of adipocyte origin have been proven to be most effective. Alternatively, surgery to obturate the fistulous tract, such as rectal advancement flap or intersphincteric ligation, may be proposed.