Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of hematological malignancies characterized by poor prognosis and advanced stages at diagnosis. The development of drug resistance in PTCL leads to relapsed or refractory cases, resulting in unsatisfactory treatment outcomes. This review discusses the mechanisms contributing to PTCL treatment resistance, including tumor heterogeneity, the tumor microenvironment (TME), and abnormal signaling pathways. It also examines existing drugs aimed at overcoming resistance and their potential mechanisms. Additionally, ongoing clinical trials related to PTCL are summarized to aid clinicians in making informed treatment decisions. The article highlights the challenges in understanding and treating PTCL, emphasizing the need for further research to improve treatment efficacy.Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of hematological malignancies characterized by poor prognosis and advanced stages at diagnosis. The development of drug resistance in PTCL leads to relapsed or refractory cases, resulting in unsatisfactory treatment outcomes. This review discusses the mechanisms contributing to PTCL treatment resistance, including tumor heterogeneity, the tumor microenvironment (TME), and abnormal signaling pathways. It also examines existing drugs aimed at overcoming resistance and their potential mechanisms. Additionally, ongoing clinical trials related to PTCL are summarized to aid clinicians in making informed treatment decisions. The article highlights the challenges in understanding and treating PTCL, emphasizing the need for further research to improve treatment efficacy.