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We report a genome-wide association study in 8406 participants of the Atherosclerosis Risk in Communities Study, identifying 41 loci associated with 92 eicosanoids and related metabolites. These findings highlight loci required for eicosanoid biosynthesis, including <jats:italic>FADS1-3<\/jats:italic>, <jats:italic>ELOVL2<\/jats:italic>, and numerous <jats:italic>CYP450<\/jats:italic> loci. In addition, significant associations implicate a range of non-oxidative lipid metabolic processes in eicosanoid regulation, including at <jats:italic>PKD2L1\/SCD<\/jats:italic> and several loci involved in fatty acyl-CoA metabolism. Further, our findings highlight select clearance mechanisms, for example, through the hepatic transporter encoded by <jats:italic>SLCO1B1<\/jats:italic>. Finally, we identify eicosanoids associated with aspirin and non-steroidal anti-inflammatory drug use and demonstrate the substantial impact of genetic variants even for medication-associated eicosanoids. 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