Skeletal muscle insulin resistance manifests as a decreased ability of insulin to stimulate glucose uptake in consequence of an impairment in its intracellular signaling. Sirtuin 1 (SIRT1), which belongs to the family of sirtuins (Sir2; silent information regulator 2 protein) participates in the regulation of skeletal muscle glucose and lipid metabolism. Experimental studies indicate that SIRT1 may play a role in the pathogenesis of skeletal muscle insulin resistance. SIRT1 directly influences insulin signal transduction pathway. It increases insulin-dependent IRS2 phosphorylation and Akt activation. Moreover, SIRT1 interacts with PGC1α and AMPK to stimulate muscle glucose uptake and fatty acid oxidation and thus it can prevent insulin resistance. SIRT1 activators might be useful in the treatment of insulin resistance-related diseases.