This paper briefly documents the history of the discovery of the EPR (enhanced permeability and retention) effect and elucidates an analogy between bacterial infection involving proteases that trigger kinin generation and cancer. The EPR effect of macromolecules in cancer tissues is defined, and the distinction between the EPR effect (with reference to clearance of macromolecules from the interstitial space of tumor tissues) and the simple passive targeting of drugs to tumors is described. Additional points of discussion include the uniqueness of tumor vessels, the influence of kinin and other vascular mediators such as nitric oxide (NO) and prostaglandins, and the heterogeneity of the EPR effect. Two different strategies to augment the EPR effect that were discovered are elevating blood pressure artificially via slow infusion of angiotensin II and applying nitroglycerin or other NO donors. Use of the nitroagent increased not only the blood flow of the tumor, but also the delivery of drug to the tumor and the drug's therapeutic effect. This finding shows an intriguing analogy to hypoxic cardiac infarct tissue, in that both are improved by NO. These two methods were applied to treatment of rodents and human cancers, in combination with other anticancer agents, with successful results achieved in rodents as well as humans. These data suggest very appealing prospects for utilization of the EPR effect in future development of cancer therapeutics.