Nanotechnology has been widely used in the development of new strategies for drug delivery and cancer therapy. Compared with traditional drug delivery systems, nano-systems have greater potential in many areas, such as multiple targeting functionalization, in vivo imaging, combined drug delivery, longer circulation time and systemic control release. Nano-systems incorporating stimulus-responsive materials have remarkable properties which allow them to bypass biological barriers and achieve targeted intracellular drug delivery. As a result of the active metabolism of tumor cells, the tumor microenvironment (TME) is highly specific with unique bio-characteristics compared to normal tissues. Environmental friendly nano-systems have now been developed in which drug release is specifically triggered by the various unique tumor environmental properties. Some of these have been translated from the bench to clinical application and have been approved by the Food and Drug Administration (FDA) for treatment of various cancerous diseases. With deeper understanding of the difference between normal and tumor tissues, it might be possible to design even more promising multiple-responsive nano-systems for drug delivery and cancer therapy in the future.