Oxylipins are a class of lipids encompassing the oxygenated metabolites of polyunsaturated fatty acids (PUFAs). As current biochemical analytical techniques have enabled the high-throughput quantification of whole profiles of oxylipins from biological samples, the interpretation of this data has posed a challenge to researchers. The studies presented here will consist of three different contexts in which oxylipin analysis was improved by integrating data layers from other omics analyses, clinical data, or oxylipins in other tissues. Specifically, multi-omics analysis of the hearts of rats orally exposed to the cardiotoxic food contaminant 2-monochloropropane-1,3-diol (2-MCPD) identified upregulation of immune response pathways and downregulation of energy metabolism and cardiac function. The inflammatory nature of 2-MCPD-induced cardiotoxicity included the suppression of anti-inflammatory docosahexaenoic acid (DHA)-derived oxylipins. The integration of the oxylipin data with transcriptomic data elucidated the suppression of DHA oxylipins by identifying dysregulation of secreted phospholipase A2, which has substrate preference for DHA. In another analysis rats were exposed to 2-MCPD with and without adequate dietary α-linolenic acid (ALA), the essential dietary n-3 PUFA. This study demonstrated that dietary ALA modulated oxylipins, enhancing n-3 PUFA-derived oxylipins in the heart, liver, kidney, and serum, while 2-MCPD exposure elevated pro-inflammatory arachidonic acid-derived oxylipins in heart and possibly liver. Adequate ALA revealed 2-MCPD exposure reduced cardiac DHA oxylipins, not apparent in the ALA-deficient diet. Integration of the oxylipin profiles across tissues identified 3-hydroxy-octadecatrienoic acid-γ (13-HOTrE-γ) as the top contributor to the distinct oxylipin profiles induced by 2-MCPD exposure, thus highlighting 13-HOTrE-γ’s association with 2-MCPD exposure across tissues. The final study analyzed valvular and plasma oxylipins from patients with severe calcific aortic valve stenosis (AVS). Valvular oxylipins were found to be broadly increased with AVS severity. The integration of the oxylipin data with clinical data, which included AVS risk factors, made for a more robust model by controlling for these factors, and enabled the identification of specific associations of arachidonic acid derived prostanoids with AVS severity markers. These studies contribute to the molecular understanding of lipid metabolism pathways altered by toxic exposure, diet, and disease, as well as providing a framework for integration of oxylipins into the omics framework.