The ectopic deposition of lipid molecules in tissues not suited for fat storage drives the tissue dysfunction that underlies diabetes and heart disease. Of the myriad lipids that accumulate, sphingolipids such as ceramides are amongst the most deleterious, as they modulate signaling and metabolic pathways to drive insulin resistance and dyslipidemia while promoting aggregation and subendothelial retention of lipoproteins within blood vessel walls. Indeed, inhibition of ceramide biosynthesis in rodents ameliorates insulin resistance, hypertriglyceridemia, atherosclerosis, hepatic steatosis, type 2 diabetes, and heart failure. Moreover, ceramide degradation is a primary means by which adiponectin receptors, which are ligand-activated ceramidases, exert their antidiabetic, cardioprotective, and insulin-sensitizing actions. Owing to a strong association of serum ceramides with insulin resistance and major adverse cardiac events, the Mayo Clinic is now marketing tests to measure circulating ceramides as markers of cardiovascular mortality. Because of these findings, ceramide synthesis inhibitors are being explored as novel therapeutics. Scott A. Summers, PhD, reviews these data and discusses new therapeutic approaches to lower ceramides and combat diabetes and its comorbidities.