This chapter reviews the main chemotherapeutic strategies used against human infections caused by agents responsible for the most important chronic viral illnesses, namely hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). There is no doubt that most current knowledge about combination antiviral therapy has been developed in the battle against HIV. The availability of more than 20 antiretroviral drugs has permitted to explore their efficacy when given in combination, an opportunity that unfortunately has only been possible since recent years for chronic hepatitis C and still is in the early stages for chronic hepatitis B. However, new antiviral compounds targeting each of these viruses are developed rapidly and will provide further opportunities to explore the efficacy of combination antiviral therapy. While sufficient suppression of HIV RNA and HBV DNA can only be achieved by long-term administration of potent antiviral drugs, HCV RNA may be completely eradicated from the infected individual after a limited duration of treatment.