Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the three most common chronic viral infections seen in the world. All three viruses share modes of transmission and hence co-exist in the same host at significantly high rates. HIV-induced immunosuppression has deleterious effects on the natural history, pathophysiology, diagnosis, therapeutic responses to hepatitis viruses. Responses to HBV vaccination are impaired in persons with HIV infection. Co-infection with the hepatitis viruses and HIV is likely to become a major health care catastrophe in the coming years. This review discusses the current trends in the understanding of the biology of co-infection and implications for treating these viruses effectively.