Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of hematological malignancies, with poor prognosis and limited treatment options. This review discusses the mechanisms of PTCL treatment resistance, including tumor heterogeneity, tumor microenvironment, and abnormal signaling pathways. It also covers existing drugs aimed at overcoming resistance, their resistance mechanisms, and ongoing clinical trials. PTCL is often resistant to standard chemotherapy, with approximately 70% of patients developing relapsed or refractory disease after first-line therapy. Treatment resistance in PTCL arises from a complex cancer ecosystem, including heterogeneous cancer cells and their surrounding tumor microenvironment. The WHO classifies PTCL into approximately 30 types, with the most common being PTCL-nos, ALCL, and AITL. The prognosis of PTCL varies depending on the subtype, with some being more aggressive than others. The tumor microenvironment plays a significant role in treatment resistance, with PD-L1 expression being particularly high in PTCL. Tumor-associated macrophages and regulatory T cells also contribute to resistance. Multiple drug resistance (MDR) is a common mechanism in PTCL, with the ABC transporter family playing a key role. The PI3K/AKT/mTOR pathway and NF-κB signaling are also involved in PTCL pathogenesis and resistance. Epigenetic changes and microRNAs are also implicated in PTCL resistance. Approved and emerging therapies for relapsed/refractory PTCL include CD30 monoclonal antibodies, pralatrexate, PD-1/PD-L1 inhibitors, and histone deacetylase inhibitors. Despite these advances, PTCL remains a challenging disease with poor prognosis, and further research is needed to develop more effective treatments.Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of hematological malignancies, with poor prognosis and limited treatment options. This review discusses the mechanisms of PTCL treatment resistance, including tumor heterogeneity, tumor microenvironment, and abnormal signaling pathways. It also covers existing drugs aimed at overcoming resistance, their resistance mechanisms, and ongoing clinical trials. PTCL is often resistant to standard chemotherapy, with approximately 70% of patients developing relapsed or refractory disease after first-line therapy. Treatment resistance in PTCL arises from a complex cancer ecosystem, including heterogeneous cancer cells and their surrounding tumor microenvironment. The WHO classifies PTCL into approximately 30 types, with the most common being PTCL-nos, ALCL, and AITL. The prognosis of PTCL varies depending on the subtype, with some being more aggressive than others. The tumor microenvironment plays a significant role in treatment resistance, with PD-L1 expression being particularly high in PTCL. Tumor-associated macrophages and regulatory T cells also contribute to resistance. Multiple drug resistance (MDR) is a common mechanism in PTCL, with the ABC transporter family playing a key role. The PI3K/AKT/mTOR pathway and NF-κB signaling are also involved in PTCL pathogenesis and resistance. Epigenetic changes and microRNAs are also implicated in PTCL resistance. Approved and emerging therapies for relapsed/refractory PTCL include CD30 monoclonal antibodies, pralatrexate, PD-1/PD-L1 inhibitors, and histone deacetylase inhibitors. Despite these advances, PTCL remains a challenging disease with poor prognosis, and further research is needed to develop more effective treatments.