Recent advances in lipidomics and metabolomics have unveiled the complexity of fatty acid metabolism and the fatty acid lipidome in health and disease. A growing body of evidence indicates that imbalances in the metabolism and level of fatty acids drive the initiation and progression of central nervous system (CNS) disorders such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. Here, we provide an in-depth overview on the impact of the β-oxidation, synthesis, desaturation, elongation, and peroxidation of fatty acids on the pathophysiology of these and other neurological disorders. Furthermore, we discuss the impact of individual fatty acids species, acquired through the diet or endogenously synthesized in mammals, on neuroinflammation, neurodegeneration, and CNS repair. The findings discussed in this review highlight the therapeutic potential of modulators of fatty acid metabolism and the fatty acid lipidome in CNS disorders, and underscore the diagnostic value of lipidome signatures in these diseases.