The hepoxilin pathway was discovered over two decades ago. Products in this pathway are derived through the 12S-lipoxygenase/hepoxilin synthase enzyme system and contain intrinsic biological activity. This activity relates to the reorganization of calcium and potassium ions within the cell, and in inflammation and insulin secretion. Although the natural hepoxilins are chemically unstable, chemical analogues (PBTs) have been synthesized with chemical and biological stability. The PBTs antagonize the natural hepoxilins. The PBTs showed bioavailability, excellent tolerance and stability in vivo. In proof of principle studies in vivo in animal models, the PBTs have shown actions as anti-inflammatory agents, anti-thrombotic agents, anti-cancer agents and anti-diabetic agents. These studies demonstrate the effectiveness of the base structure of the hepoxilin (and PBT) molecule and serve as an excellent framework for the design and preparation of second-generation compounds with improved pharmaceutical properties as therapeutics for the above-mentioned diseases.