The aim of this work was to investigate if and how (i) dietary lipids and Cd affect fatty acid homeostasis and metabolism, (ii) the individual/tissue/cell fatty acid profile modulates the Cd sensitivity, in rainbow trout (Oncorhynchus mykiss) and the large water flea (Daphnia magna), using both in vitro and in vivo approaches. We successfully modulated the fatty acid profile of the experimental models. Overall, both the fatty acid supply and the Cd exposure influenced fatty acid homeostasis and metabolism. The fatty acid profile influenced individual/tissue and cell sensitivity to Cd. In vitro enrichments in specific polyunsaturated fatty acids (PUFA) (e.g. alpha-linolenic acid (ALA, 18:3n-3) and eicosapentaenoic acid (EPA, 20:5n-3)) conferred protection against Cd while enrichment in others (e.g. linoleic acid (LA, 18:2n-6)) had no impact. PUFA-derived cytoprotection was not linked to a reduced cell Cd burden but would rather occur through a reduction of the oxidative stress induced by Cd and a differential induction of the eicosanoid cascade. In vivo, rainbow trout fed the ALA- and EPA-enriched diets seemed to be respectively the least and the most affected by Cd. Fish fed the ALA-enriched diet had a higher detoxifying ability against Cd and a lower hepatic Cd burden. In contrast, fish fed the EPA-enriched diet had impaired growth performances and a decreased total hepatic antioxidant capacity under Cd exposure. In vivo, liposome feeding increased adult daphnid tolerance to Cd. The presence of EPA in liposomes did not increase adult tolerance to Cd. Offspring's tolerance to Cd was influenced by the brood number and the maternal diet. It was positively correlated with the PUFA level in body neutral lipids, especially ALA. Overall, this work provides new information about interactions between the nature of dietary lipids and the biological responses to Cd in aquatic biota.