The focus of the XII International Conference on AIDS in Geneva will deal with treatment failures. The protease inhibitors have been as successful as predicted two years ago, and their failures may be predicted using several factors. Long-term strategies are essential to successfully treat patients. All treatments can suppress the virus immediately, perhaps for decades, however, the issue of treatment failure needs to be addressed. Early and aggressive treatment was used as a possibility of a cure, however, the scenario is not likely. Current guidelines suggest that high viral loads predict rapid disease progression and death. At some point, that philosophy collides with quality of life issues. Now, the preferred approach is combination treatment, including a protease inhibitor and two nucleoside analogs. Nonadherence is the single most important risk factor in predicting failure. For that reason, it is preferable to prescribe doses that can be taken less frequently. Switching treatments is necessary when viral load climbs, but it is often difficult to design an effective and tolerable alternative therapy. New drugs in the pipeline are briefly described, including abacavir (Ziagen), efavirenz (Sustiva), adefovir (Preveon), and amprenavir (141W94). Strategies for successful therapy are listed, emphasizing the need to minimize the development of drug resistance.