The spectrum of drugs used in HIV-infected patients has dramatically changed since triple antiretroviral combinations were introduced, albeit at the expense of some severe adverse events, in 1996. Abandonment of stavudine in countries that can afford it, new drugs from new classes with a wide therapeutic window and the impressive scale-up of drug access in resource-limited settings are several of the key new events. Drug safety is likely to be the most important factor to distinguish one antiretroviral regimen from another. We review life-threatening adverse events, adverse events of new investigational or recently marketed drugs, adverse events with a genetic component and tissue-specific adverse events of fat, heart, bone, kidney and liver.