Hepatitis C virus (HCV) infection is transmitted by injection drug use and associated with psychiatric conditions. Patients with drug use or significant psychiatric illness have typically been excluded from HCV treatment trials noting the 1997 National Institutes of Health Consensus Statement on HCV that indicated active drug use and major depressive illness were contraindications to treatment of HCV infection. However, the 2002 NIH Consensus Statement recognized that these patients could be effectively treated for HCV infection and recommended that treatment be considered on a case-by-case basis. Treating HCV infection in these patients is challenging, with drug use relapse possibly leading to psychosocial instability, poor adherence, and HCV reinfection. Interferon therapy may exacerbate preexisting psychiatric symptoms. Co-occurring human immunodeficiency virus or hepatitis B virus provide additional challenges, and access to ancillary medical and psychiatric services may be limited. Patients with co-occurring HCV infection, substance use, and psychiatric illness can complete interferon treatment with careful monitoring and aggressive intervention. Clinicians must integrate early interventions for psychiatric conditions and drug use into their treatment algorithm. Few programs or treatment models are designed to manage co-occurring substance use, psychiatric illness, and HCV infection and therapy. The National Institute on Drug Abuse convened a panel of experts to address the current status and the long-range needs through a 2-day workshop, Co-occurring Hepatitis C, Substance Abuse, and Psychiatric Illness: Addressing the Issues and Developing Integrated Models of Care. This conference report summarizes current data, medical management issues, and strategies discussed.