This Special Issue on the enhanced permeability and retention (EPR) effect commemorates the 35th anniversary of its discovery, the original 1986 Matsumura and Maeda finding being published in Cancer Research as a new concept in cancer chemotherapy . My review here describes the history and heterogeneity of the EPR effect, which involves defective tumor blood vessels and blood flow . We reported that restoring obstructed tumor blood flow overcomes impaired drug delivery, leading to improved EPR effects . I also discuss gaps between small animal cancers used in experimental models and large clinical cancers in humans, which usually involve heterogeneous EPR effects, vascular abnormalities in multiple necrotic foci, and tumor emboli . Here, I emphasize arterial infusion of oily formulations of nanodrugs into tumor-feeding arteries, which is the most tumor-selective drug delivery method, with tumor/blood ratios of 100-fold . This method is literally the most personalized medicine because arterial infusions differ for each patient, and drug doses infused depend on tumor size and anatomy in each patient . Future developments in EPR effect-based treatment will range from chemotherapy to photodynamic therapy, boron neutron capture therapy, and therapies for free radical diseases . This review focuses on our own work, which stimulated numerous scientists to perform research in nanotechnology and drug delivery systems, thereby spawning a new cancer treatment era.