Current recommendations for the treatment of HIV-infected patients advise highly active antiretroviral therapy (HAART) consisting of combinations of 3 or more drugs to provide long-term clinical benefit. This is because only a complete suppression of virus replication will be able to prevent virus drug resistance, the main cause of drug failure. Virus drug resistance may remain a cause of concern in patients who have already received suboptimal mono- or bitherapy, or for patients who do not experience complete shut-down of virus replication under HAART. For these patients, replacement of one combination therapy regimen by another at drug failure, taking into account the existing resistance profile, will be needed. The development of new drugs will remain necessary for those patients who have failed to respond to all currently available drugs, as will be the institution of more effective and less toxic HAART regimens.