HtrA serine peptidase 2 (HTRA2) is a serine protease existing in the mitochondrial gap. Among the four members of the human HtrA serine peptidase family, HTRA2 is the only protease with clear localization in the cell. It plays a dual role in the maintenance of mitochondrial homeostasis and the promotion of cell apoptosis. HTRA2 has been found to be associated with a variety of tumors. Meanwhile, the expression of HTRA2 can enhance the sensitivity of chemotherapy and radiotherapy, and can be used as a diagnostic and prognostic marker for malignant tumors and a target for combined therapy. This article reviews the structure, biological function and role of HTRA2 in malignant tumors, in order to provide clues and basis for early diagnosis and individualized treatment of tumor patients.