Ceramides are products of metabolism that accumulate in individuals with obesity or dyslipidaemia and alter cellular processes in response to fuel surplus. Their actions, when prolonged, elicit the tissue dysfunction that underlies diabetes and heart disease. Here, we review the history of research on these enigmatic molecules, exploring their discovery and mechanisms of action, the evolutionary pressures that have given them their unique attributes and the potential of ceramide-reduction therapies as treatments for cardiometabolic disease.