Ceramide forms the backbone of all complex sphingolipids and has been the focus of considerable attention in the past few years due to the discovery that ceramide plays vital roles as an intracellular messenger. Ceramide, which consists of a sphingoid long chain base to which a fatty acid is N-acylated, is synthesized in mammals by a family of ceramide synthases (CerS), each of which uses a restricted subset of fatty acyl CoAs for N-acylation. Sphingolipids are found at high levels in nervous tissue, where they perform a variety of important functions in both the adult and the maturing brain. We now review what is known about the role of the acyl chain composition of ceramides and sphingolipids in normal brain development and in neurological diseases. Specifically, we attempt to integrate the information that is available about CerS expression and activity in the brain with the changes in the acyl chain composition of ceramide and complex sphingolipids in a number of neurodegenerative diseases and conditions, such as metachromatic leukodystrophy, neuronal ceroid lipofuscinoses, HIV infection, aging, Alzheimer’s disease, ischemia, and epilepsy. We conclude that understanding the direct relationship between the CerS proteins and neurological conditions will be of great importance for delineating the precise roles of sphingolipids in the brain and is likely to be the subject of intense research activity in the years ahead.