Nanomedicines have long been expected to significantly enhance cancer treatment. However, their clinical translation is still very limited despite of the world's great efforts during the last 2 decades. One of the reasons is that the transport barriers within tumors restrict their penetration into tumors, with most nanomedicines remaining among the top submicrometer to several micrometers scale. Therefore, there is an extensive interest in the field to understand the tumor microenvironment and develop techniques to boost the penetration of nanomedicines in tumors. This review emphasizes the need of smart nanotechnology to fit the changing requirements of nanomedicines for effective drug delivery, particularly the technologies for deep penetration of nanomedicines in tumor tissues, and explores their mechanisms in order to achieve multistage requirement during the applications of nanomedicines in patients. Finally, the advantages and