Dietary essential omega-6 ( -6) and omega-3 ( -3) 18 carbon (18C-) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), can be converted (utilizing desaturase and elongase enzymes encoded by and genes) to biologically-active long chain (LC; >20)-PUFAs by numerous cells and tissues. These -6 and -3 LC-PUFAs and their metabolites (ex, eicosanoids and endocannabinoids) play critical signaling and structural roles in almost all physiologic and pathophysiologic processes. This review summarizes: (1) the biosynthesis, metabolism and roles of LC-PUFAs; (2) the potential impact of rapidly altering the intake of dietary LA and ALA; (3) the genetics and evolution of LC-PUFA biosynthesis; (4) Gene-diet interactions that may lead to excess levels of -6 LC-PUFAs and deficiencies of -3 LC-PUFAs; and (5) opportunities for precision nutrition approaches to personalize -3 LC-PUFA supplementation for individuals and populations. The rapid nature of transitions in 18C-PUFA exposure together with the genetic variation in the LC-PUFA biosynthetic pathway found in different populations make mal-adaptations a likely outcome of our current nutritional environment. Understanding this genetic variation in the context of 18C-PUFA dietary exposure should enable the development of individualized -3 LC-PUFA supplementation regimens to prevent and manage human disease.