HIV therapy has well-established and substantial clinical benefits. Awareness of these benefits has brought many infected persons into care. Many more infected persons would be treated were it not for the frequent side effects associated with antiretroviral drugs. All antiretroviral agents can cause both short-term and long-term toxicities. This is a particularly vexing problem as current data does not allow accurate predictions of treatment toxicities and, in many cases, side effects are only partially reversible. Moreover, therapy is frequently associated with the selection of drug-resistant viral isolates and incomplete viral suppression. This is commonly caused by inadequate medication adherence and leads to increasingly severe virologic failure. The present review will address both the striking advantages of HIV therapy as well as the ongoing challenges in its application.