It has been known for decades that the regulation of sphingolipids (SLs) is essential for the proper function of many cellular processes. However, a complete understanding of these processes has been complicated by the structural diversity of these lipids. A well-characterized metabolic pathway is responsible for homeostatic maintenance of hundreds of distinct SL species. This pathway is perturbed in a number of pathological processes, resulting in derangement of the "sphingolipidome." Recently, advances in mass spectrometry (MS) techniques have made it possible to characterize the sphingolipidome in large-scale clinical studies, allowing for the identification of specific SL molecules that mediate pathological processes and/or may serve as biomarkers. This manuscript provides an overview of the functions of SLs, and reviews previous studies that have used MS techniques to identify changes to the sphingolipidome in non-metabolic diseases. (C) 2018 Elsevier Inc. All rights reserved.