Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers. Its clinical management remains unclear and few preclinical data are available on its underlying pathophysiology. The therapeutic strategy is difficult to establish because few prospective and randomized trials are available. In this review, we report on the clinical presentation and pathophysiology of radiation cystitis. Then we discuss potential therapeutic approaches, with a focus on the immunopathological processes underlying the onset of radiation cystitis, including the fibrotic process. Potential therapeutic avenues for therapeutic modulation will be highlighted, with focus on the interaction between mesenchymal stromal cells and macrophages for the prevention and treatment of radiation cystitis.