A commonly cited cause of poor adherence to highly active antiretroviral therapy (HAART) is adverse drug reactions. Short-term adverse effects are potential threats to successful introduction and maintenance of HAART. The long-term toxicities of HAART are still emerging and being defined, as evidenced by the recently described metabolic disorders (i.e., the syndrome of maldistribution, hyperlipemia, glucose intolerance and insulin resistance). With 14 licensed agents in 2000, other agents in common use, and numerous combinations of >/=3 drugs, awareness and recognition of adverse effects are increasingly important for clinicians and patients. The common adverse drug reactions encountered with HAART, including new agents and their impact on patient adherence, are reviewed. Current strategies to anticipate and mitigate adverse effects are summarized.