For almost four decades, the enhanced permeability and retention (EPR) effect has served as the foundation for passive targeting in cancer nanomedicine. While preclinical studies have reported promising nanoparticle accumulation and therapeutic benefits, clinical success has remained limited, with only modest improvements in patient survival and outcomes. One major challenge is the significant biological difference between animal models and human tumors. In xenograft studies, nanoparticles often accumulate at levels above 5-10% of the injected dose, whereas clinical studies typically report only about 0.7%, highlighting the poor translation of preclinical findings. Moreover, growing evidence suggests that nanoparticle delivery is not solely driven by passive leakage through tumor blood vessels but also involves active endothelial transcytosis. These findings indicate that the EPR effect should be viewed as a context-, patient-, and tumor-specific phenomenon rather than a universal targeting mechanism. To overcome current limitations, researchers are exploring strategies such as vascular reprogramming, controlled delivery techniques, synergistic therapies, and active transport and retention (ATR). Together with stimuli-responsive nanocarriers, imaging biomarkers, computational modeling, and improved patient stratification, these advances could support the development of more effective and personalized cancer nanomedicines.