Much has been made about JLW Thudichum’s colorful, and one could say clairvoyant, naming of sphingosine “in commemoration of the many enigmas which it presented to the inquirer” in his 1884 treatise The Chemistry of the Brain1 because many of the riddles of sphingolipids (as the broader field was later named) 2 remained unanswered for the following century. This changed radically over the past several decades as researchers explored, and ultimately established, what seemed at the time to be radical concepts: that sphingolipids are not just structural elements of cells but also participate in intra-and extracellular signaling; that not only the complex glycan headgroups, but also the lipid backbones, are highly specified metabolically and have selective biochemical functions; and that even the longest known function of these lipids, as structural components of the “fluid mosaic” of cell membrane lipids, is not so simple, and often involves the dynamic clustering of sphingolipids in nontraditional microdomains referred to as rafts. We still know only a fraction of their secrets, but this enlightenment has defined models for thinking about these compounds that remove them from their enigmatic “black box.” Now, a major challenge is to keep up with the rapid growth in knowledge about the sphingolipidome, that is, the ensemble of all sphingolipids. 3 A major goal of the review is to help the reader more easily grasp the metabolic interrelationships that account for the tens of thousands of molecular subspecies (and perhaps more) that appear in nature, with a focus on mammals. The magnitude of this subject precludes the inclusion of all of the enzymes and metabolites, and the author apologizes for the omission of many