Abstract: Tumor occurrence is usually recognized as the interplay between genetic variations within the tumor and the environment. During a long time, great effort has been made in killing cancer cells. However, the role of tumor microenvironment has been largely ignored, which plays an important role in tumor generation, growth, invasion and metastasis. Meanwhile, tumor microenvironment not only facilitates the tumor infiltration, but also promotes the exchange of enzymes and cytokines to aid tumor proliferation, differentiation and self-renewal. Thus, better understanding of tumor microenvironment shows great importance. Recent developments in nanotechnology have brought new approaches to cancer diagnosis and therapy. Nanoparticles were suggested to show enhanced efficacy, while simultaneously reducing side effects and promoting bioavailability, owing to properties such as tumor localization and active cellular uptake. Additionally, nanoparticle surface chemistry has evolved from conventional synthetic polymers to more biologically inspired strategies, including cell membrane and self-recognition peptides, to minimize nonspecific uptake of nanoparticles. In the current review, we highlight the targets in tumor microenvironment and the strategies of nano drug delivery system to target tumor microenvironment for the treatment of cancer. We also highlight design considerations to improve nano drug delivery.