Cytochrome P450 (CYP) epoxygenases are a special subset of heme-containing CYP enzymes capable of performing the epoxidation of polyunsaturated fatty acids (PUFA) and the metabolism of xenobiotics. This dual functionality positions epoxygenases along a metabolic crossroad. Therefore, structure-function studies are critical for understanding their role in bioactive oxy-lipid synthesis, drug-PUFA interactions, and for designing therapeutics that directly target the epoxygenases. To better exploit CYP epoxygenases as therapeutic targets, there is a need for improved understanding of epoxygenase structure-function. Of the characterized epoxygenases, human CYP2J2 stands out as a potential target because of its role in cardiovascular physiology. In this review, the early research on the discovery and activity of epoxygenases is contextualized to more recent advances in CYP epoxygenase enzymology with respect to PUFA and drug metabolism. Additionally, this review employs CYP2J2 epoxygenase as a model system to highlight both the seminal works and recent advances in epoxygenase enzymology. Herein we cover CYP2J2's interactions with PUFAs and xenobiotics, its tissue-specific physiological roles in diseased states, and its structural features that enable epoxygenase function. Additionally, the enumeration of research on CYP2J2 identifies the future needs for the molecular characterization of CYP2J2 to enable a new axis of therapeutic design.