 Despite the development of numerous anticancer compounds targeting cancer cell proliferation and metabolism, chemotherapy for human solid tumors remains unsatisfactory due to the lack of selective delivery of these compounds into solid tumor tissue. The enhanced permeability and retention effect, EPR effect, describes a universal mechanism in which macromolecular compounds beyond certain sizes can accumulate in the tumor vascularized area. But targeting therapy via the EPR effect is not always successful due to variations in the strength of the EPR effect depending on various factors. This review emphasizes the significance of the EPR effect and discusses methods for optimizing its use in developing smarter macromolecular nanomedicine for clinical applications. This article was authored by Jun Wu.