Treatment-resistant depression (TRD) is a severe mental illness that poses a significant threat to the health and well-being of patients. In recent years, TRD has garnered increased attention from scholars both domestically and internationally. Currently, there is ongoing debate regarding the definition of TRD. Clinical treatment strategies for TRD primarily include optimizing drug dosage and duration, switching medications, combining drugs, and employing synergistic therapies. Additionally, various animal models of TRD, based on different pathological changes, have been successfully established and utilized in research to reveal the potential pathogenesis of TRD, such as excessive inflammatory responses, hyperactivity of the hypothalamic-pituitary-adrenal axis, dysregulation of the glutamatergic system, and disturbances in tryptophan metabolism. These findings have generated new insights for the development of novel medications for TRD, with some candidates currently in the pipeline having achieved significant breakthroughs. This review comprehensively discusses these issues, aiming to provide a reference for future research and drug development in TRD.