Lipid abnormalities such as obesity, increased circulating free fatty acid levels, and excess intramyocel-lular lipid accumulation are frequently associated with insulin resistance. These observations have prompted investigators to speculate that the accumulation of lipids in tissues not suited for fat storage (e.g., skeletal muscle and liver) is an underlying component of insulin resistance and the metabolic syndrome. We review the metabolic fates of lipids in insulin-responsive tissues and discuss the roles of specific lipid metabolites (e.g., ceramides, GM3 gan-glioside, and diacylglycerol) as antagonists of insulin signaling and action