Abstract: As a typical hallmark of solid tumor, hypoxia is not only strongly associated with angiogenesis and tumor metastasis, but also likely to produce tolerance of cancer cells, thus reducing the therapeutic effects of cancer therapies such as chemotherapy, radiotherapy and photodynamic therapy. Nevertheless, low oxygen level and highly bioreductive microenvironment offer us the potential opportunities to design hypoxia-responsive antitumor nanomedicines. This review briefly summarizes the development of hypoxia-activated prodrugs and their therapeutic strategies, with special attention to the novel hypoxia-responsive nano-drug delivery systems that have emerged in recent years, so as to pave a new way for antitumor clinical research.