Deaths from hepatitis C virus (HCV)–related disease are increasing, now exceeding those from human immunodeficiency virus. Up to 7 million Americans (2.3%) may be infected with HCV, and more than half are undiagnosed. Proposed expansion of hepatitis C screening to include all persons born between 1945 and 1965 will lead to many new diagnoses, and infectious diseases physicians have a unique opportunity to be part of managing these patients. Apart from a liver-focused history and examination, the initial evaluation includes determination of the liver function via serum tests and assessment of liver fibrosis and necroinflammation through biopsy or noninvasive means. Patients with cirrhosis require screening for esophageal varices and for liver cancer. Nonimmune patients need vaccinations against hepatitis A and B, and alcohol abstinence is critical. Initial counseling on therapy emphasizes viral cure rates of currently 70%–80% as well as expected side effects. New treatments with fewer side effects and potentially higher cure rates are currently in development.