Since the first acquired immune deficiency syndrome (AIDS) patient reported over 25 years ago, a number of antiretroviral agents have been generated for the fight with AIDS. Combination chemotherapy combining such antiretroviral agents has had a major impact on the morbidity and mortality of AIDS patients. However, we have faced multiple major problems in AIDS therapy. Those problems represent the challenges different than we faced in the development of the first drug. We are obviously at a new forefront in the therapy of HIV infection. Further improved approaches to explore new treatment modalities should be continued in the hope that with new and more potent antiviral agents, we will be able to control HIV diseases more efficiently and effectively.