Antiretroviral drug resistance and adverse events represent ongoing challenges in the management of HIV infection. The introduction of the integrase inhibitor raltegravir, the chemokine receptor antagonist maraviroc, the nonnucleoside reverse transcriptase inhibitor (NNRTI) etravirine, and the protease inhibitor (PI) darunavir represent important advances in the treatment of patients who have HIV/AIDS and extensive drug resistance or intolerance. Raltegravir has been shown to be as effective as efavirenz with the advantage of a better adverse-effect profile. Maraviroc has been shown to be effective-in combination therapy-for (early-stage) CCR5-tropic HIV-1 infection in adults with resistance to multiple agents. Etraviri-ne is designed to circumvent resistance to NNRTIs caused by certain viral mutations. Darunavir, like other PIs, prevents maturation of new virus particles. The pharmacokinetics, clinical evidence on efficacy, resistance, closing, and adverse effects of these new agents are discussed in this article. [Infect Med. 2009;26:113-120]