Patients with hepatitis C who are treated with interferon may develop neuropsychiatric symptoms, including fatigue and depression. The authors discuss the potential use of functional neuroimaging in the identification and treatment of these patients. The authors provide an overview of functional neuroimaging studies of fatigue and depressive symptoms in various medical and psychiatric conditions and suggest future directions for research that may increase understanding of the specific neural substrates of neuropsychiatric side effects associated with hepatitis C and interferon treatment. This knowledge may help consultation-liaison psychiatrists identify patients at high risk for developing side effects related to hepatitis C and interferon, which would allow for implementation of validated strategies for prophylactic treatment of these patients.