SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. Inflammation is associated with peripheral insulin resistance, which disrupts nutrient homeostasis and leads to diabetes. SOCS1 and SOCS3 target IRS1 and IRS2 for ubiquitin-mediated degradation. These proteins bind to IRS1 and IRS2 and promote their ubiquitination and subsequent degradation in multiple cell types. Mutations in the conserved SOCS box of SOCS1 abrogate its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. SOCS1 mutants also fail to promote the ubiquitination and degradation of IRS1 or IRS2. Adenoviral expression of SOCS1 in mouse liver reduces hepatic IRS1 and IRS2 levels and causes glucose intolerance, while SOCS1 mutants have no effect. Thus, SOCS-mediated degradation of IRS proteins, likely via the elongin BC ubiquitin-ligase, may be a general mechanism of inflammation-induced insulin resistance, providing a therapeutic target. Insulin and insulin-like growth factors exert biological effects through receptor-mediated tyrosine phosphorylation of IRS proteins, including IRS1, IRS2, IRS3, and IRS4. IRS proteins coordinate multiple signals through the PI3K → Pkb/Akt and Grb2/Sos → Ras cascades. IRS1 mediates the effects of insulin and IGF1 on somatic cell growth, while IRS2 is essential for nutrient homeostasis. Mice lacking IRS1 or IRS2 display peripheral insulin resistance, a major determinant of type 2 diabetes. However, IRS1 knockout mice do not develop diabetes due to lifelong compensatory hyperinsulinemia, whereas IRS2 knockout mice develop severe glucose intolerance and diabetes. IRS2 dysregulation is particularly problematic because it regulates transcription factors in β-cells essential for glucose sensing and insulin secretion. IRS proteins also integrate heterologous signals that negatively regulate the insulin-signaling cascade. Proinflammatory cytokines or insulin activate JNK, which promotes serine phosphorylation of IRS1 and IRS2, inhibiting coupling to the activated insulin receptor. IRS proteins are also decreased in people and rodents with diabetes. Recent studies reveal that IRS proteins are ubiquitinated and subsequently degraded by the 26S proteasome during insulin stimulation or cellular stress, but the mechanisms that recruit ubiquitin-ligases to the IRS proteins are unknown. Insulin resistance is a common consequence of physiological stress, at least in part due to the production of proinflammatory cytokines during infection or injury, pregnancy, growth and aging, or chronic obesity. Many proinflammatory cytokines up-regulate suppressors of cytokine signaling (SOCS) proteins, including eight isoforms that contain an NH2-terminal SH2 domain and a COOH-terminal SOCS box. SOCS proteins bind via their SH2 domains to activated cytokine receptorsSOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. Inflammation is associated with peripheral insulin resistance, which disrupts nutrient homeostasis and leads to diabetes. SOCS1 and SOCS3 target IRS1 and IRS2 for ubiquitin-mediated degradation. These proteins bind to IRS1 and IRS2 and promote their ubiquitination and subsequent degradation in multiple cell types. Mutations in the conserved SOCS box of SOCS1 abrogate its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. SOCS1 mutants also fail to promote the ubiquitination and degradation of IRS1 or IRS2. Adenoviral expression of SOCS1 in mouse liver reduces hepatic IRS1 and IRS2 levels and causes glucose intolerance, while SOCS1 mutants have no effect. Thus, SOCS-mediated degradation of IRS proteins, likely via the elongin BC ubiquitin-ligase, may be a general mechanism of inflammation-induced insulin resistance, providing a therapeutic target. Insulin and insulin-like growth factors exert biological effects through receptor-mediated tyrosine phosphorylation of IRS proteins, including IRS1, IRS2, IRS3, and IRS4. IRS proteins coordinate multiple signals through the PI3K → Pkb/Akt and Grb2/Sos → Ras cascades. IRS1 mediates the effects of insulin and IGF1 on somatic cell growth, while IRS2 is essential for nutrient homeostasis. Mice lacking IRS1 or IRS2 display peripheral insulin resistance, a major determinant of type 2 diabetes. However, IRS1 knockout mice do not develop diabetes due to lifelong compensatory hyperinsulinemia, whereas IRS2 knockout mice develop severe glucose intolerance and diabetes. IRS2 dysregulation is particularly problematic because it regulates transcription factors in β-cells essential for glucose sensing and insulin secretion. IRS proteins also integrate heterologous signals that negatively regulate the insulin-signaling cascade. Proinflammatory cytokines or insulin activate JNK, which promotes serine phosphorylation of IRS1 and IRS2, inhibiting coupling to the activated insulin receptor. IRS proteins are also decreased in people and rodents with diabetes. Recent studies reveal that IRS proteins are ubiquitinated and subsequently degraded by the 26S proteasome during insulin stimulation or cellular stress, but the mechanisms that recruit ubiquitin-ligases to the IRS proteins are unknown. Insulin resistance is a common consequence of physiological stress, at least in part due to the production of proinflammatory cytokines during infection or injury, pregnancy, growth and aging, or chronic obesity. Many proinflammatory cytokines up-regulate suppressors of cytokine signaling (SOCS) proteins, including eight isoforms that contain an NH2-terminal SH2 domain and a COOH-terminal SOCS box. SOCS proteins bind via their SH2 domains to activated cytokine receptors