Abstract: Polymeric nano-drug delivery system has been widely used for tumor targeting. The microenvironment of tumor tissues, different from normal tissues, is characterized by acidic pH, abundant glutathione (GSH), local hypoxia, extensive angiogenesis, irregular blood perfusion, etc. Polymeric nano-drug delivery system, designed on the basis of the characters of tumor microenvironment, could achieve deep penetration into tumor tissues, improved cellular uptake, accelerated intracellular drug release, thus increasing the anti-tumor efficacy. In this review, we mainly focused on the design principles and action mechanisms of tumor microenvironment responsive polymeric nano-drug delivery system, so as to provide reference for transformation from basic research to clinical practice.