Natural killer/T cell lymphoma (NKTCL) is a malignant tumor originating from NK or T cells, characterized by its highly aggressive and heterogeneous nature. NKTCL is predominantly associated with Epstein-Barr virus infection, disproportionately affecting Asian and Latin American populations. Owing to the application of asparaginase and immunotherapy, clinical outcomes have improved significantly. However, for patients in whom first-line treatment fails, the prognosis is exceedingly poor. Overexpression of multidrug resistance genes, abnormal signaling pathways, epigenetic modifications and active Epstein-Barr virus infection may be responsible for resistance. This review summarized the mechanisms of resistance for NKTCL and proposed potential therapeutic approaches.Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.