Fatty acids, particularly the omega-3 and omega-6 essential fatty acids (EFAs), are considered critical nutritional sources for the developing fetus. The placenta governs the fetal supply of fatty acids via two processes: transport and metabolism. Placental fatty acid metabolism can play a critical role in guiding pregnancy and fetal outcome. EFAs can be metabolized to important cell signaling molecules in placenta by several major isoform families including: the Cytochrome P450 subfamily 4A (CYP4A); Cyclooxygenases (COXs); and Lipoxygenases (LOXs). Peroxisome proliferator-activated nuclear receptors (PPARs) have been demonstrated to regulate a number of placental fatty acid/lipid homeostasis-related proteins (e.g., metabolizing enzymes and transporters). The present review summarizes research on the molecular and functional relevance of fatty acid metabolizing enzymes and the role of PPARs in regulating their expression in the mammalian placenta. Elucidating the pathways of placental fatty acid metabolism and the regulatory processes governing these pathways is critical for advancing our understanding of the role of placenta in supplying EFAs to the developing fetus and the potential implications on pregnancy and fetal outcome. A more complete understanding of placental fatty acid disposition may also provide a basis for nutritional/pharmacological interventions to ameliorate the risk of adverse pregnancy and/or fetal outcomes.