Improving survival for people with HIV has brought management of co-morbidities into focus. In the era of highly active antiretroviral therapy, co-infection with either hepatitis B virus and/or hepatitis C virus, and HIV therapies themselves, have increased liver disease-related morbidity and mortality. The dual anti-HIV and anti-hepatitis B activity of several established and emerging therapeutic agents provides the opportunity to both restore immune function and prevent liver disease progression in people with HIV-hepatitis B virus co-infection. Improving hepatitis C antiviral therapy also provides optimism around management of liver disease in people with HIV-hepatitis C virus co-infection. However, formulation of appropriate therapeutic strategies for HIV-hepatitis B and HIV-hepatitis C co-infection requires further research, including clinical trials of combination antiviral therapy with specific anti-hepatitis B and anti-hepatitis C activity. A possible role may also exist for combined antiviral and immune-based therapies.