Obesity and dyslipidemia are risk factors for metabolic disorders including diabetes and cardiovascular disease. Sphingolipids such as ceramide and glucosylceramides, while being a relatively minor component of the lipid mileu in most tissues, may be amongst the most pathogenic lipids in the onset of the sequelae associated with excess adiposity. Circulating factors associated with obesity (e.g. saturated fatty acids, inflammatory cytokines) selectively induce enzymes which promote sphingolipid synthesis, and lipidomic profiling reveals relationships between tissue sphingolipid levels and certain metabolic diseases. Moreover, studies in cultured cells and isolated tissues implicate sphingolipids in certain cellular events associated with diabetes and cardiovascular disease, including insulin resistance, pancreatic -cell failure, cardiomyopathy and vascular dysfunction. However, definitive evidence that sphingolipids contributes to insulin resistance, diabetes, and atherosclerosis has come only recently, as researchers have found that pharmacological inhibition or genetic ablation of enzymes controlling sphingolipid synthesis in rodents ameliorates each of these conditions. Herein we will review the role of ceramide and other sphingolipid metabolites in insulin resistance, cell failure, cardiomyopathy and vascular dysfunction, focusing on these in vivo studies which identify enzymes controlling sphingolipid metabolism as therapeutic targets for combating metabolic disease.