Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta-cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. With recent advances in genomic techniques, it is now possible to assess gene expression patterns in small samples of muscle tissue from metabolically characterized humans. We have applied these techniques to identify genes and pathways potentially important in the pathogenesis of DM. Both DM and the insulin resistance characteristic of "prediabetes" are associated with reduced expression of genes encoding key enzymes in oxidative metabolism and mitochondrial function, and highlight the potential central role for oxidative metabolic pathways in the pathogenesis of type 2 DM.