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Anticancer nanomedicine was coined to describe anticancer delivery systems such as polymer conjugates, liposomes, micelles, and metal nanoparticles. These anticancer delivery platforms have been developed with the enhanced permeability and retention (EPR) effect as a central mechanism for tumor targeting. EPR based nanomedicine has demonstrated, beyond doubt, to selectively target tumor tissues in animal models. However, over the last two decades, only nine anticancer agents utilizing this targeting strategy have been approved for clinical use. In this review, we systematically analyze various aspects that explain the limited clinical progress yet achieved. The influence of nanomedicine physicochemical characteristics, animal tumor models, and variations in tumor biology, on EPR based tumor targeting is closely examined. Furthermore, we reviewed results from over onehundred publications to …