Highly active antiretroviral therapy (HAART)-associated toxicity has been the most important limiting factor of the doubtless efficacy of this treatment. HAART-associated toxicity can have two kinds of temporal profiles; early toxicity, also known as tolerability, and long-term or chronic toxicity. Both types of toxicity are of foremost importance, not only because they represent an added co-morbidity, but also because the patient often associates the starting of HAART with toxic effects. This fact has often been linked to a decrease in patient adherence to the treatment, which may eventually lead to virological failure. The appearance of long-term toxic effects is usually due to continuous, even indefinite, exposure to antiretroviral drugs. When antiretroviral drug toxicity develops, the caregiver usually has two choices; to decrease and/or reverse such toxicity. On the one hand, withdrawal of the offending agent and its substitution for another agent with a different toxicity profile, and on the other, pharmacological or non-pharmacological interventions directed at correcting the toxicity-associated problems. However, it should be kept in mind that pharmacological interventions always have the possibility of giving rise to interactions with antiretroviral drugs, eventually leading to new toxic effects. Fortunately, in the last few years, new drugs and drug families have been added to the antiretroviral armamentarium. Most of these drugs have more benign toxicity profiles than first-generation antiretroviral drugs. No doubt our best hope to decrease HAART-associated toxicity relies upon treatment with these new drugs, together with the knowledge of the genetic determinants of antiretroviral drug-associated toxicity (toxicogenetics). Hopefully, toxicogenetics will be of paramount importance in the future to design new antiretroviral regimes best fitted to a given patient, in order to personalize HAART with the objective of building up more effective and less toxic regimes.