Insulin resistance (IR) is present in approximately 50% of patients with chronic hepatitis C (CHC). Beyond the well-described risk of developing diabetes, hypertension, hypertriglyceridemia, and cardiovascular disease, IR in hepatitis C is associated with hepatic inflammation, fibrosis, cirrhosis, and hepatocellular cancer. Moreover, IR is associated with a twofold to fourfold reduction in the effectiveness of viral eradication using regimens based on pegylated interferon and ribavirin. In the last decade, a direct pathogenic role for hepatitis C virus infection in IR has been discerned. Targeting IR in CHC, therefore, has the potential to reduce liver disease progression and to improve response rates to antiviral therapy. Several therapeutic interventions for the management of IR in patients with CHC have been reported, some with promising results. Although lifestyle intervention should be recommended for all patients with CHC, whether greater insulin sensitivity results in improved sustained virologic response rates to antiviral therapy is unclear. Despite encouraging data, the overall efficacy of pharmacologic approaches targeting IR to improve sustained virologic response is also not well established. This review summarizes current knowledge on the pathophysiology and management of IR and type 2 diabetes associated with hepatitis C infection.