Decisions regarding whether to start combination antiretroviral therapy (cART) during primary infection and when to initiate treatment during chronic infection continue to evolve. Although current data suggest that there may be a benefit to therapy during primary infection, results are inconclusive. Once begun, treatment probably should be continued indefinitely, since its potential advantages disappear over time if treatment is stopped. Recent studies suggest that cART may be useful at higher CD4 cell count thresholds than are currently recommended in several guidelines. Several regimens are acceptable as initial therapy, with tenofovir/emtricitabine/efavirenz favored by many because of potency and ease of administration. Other favored regimens include combinations of 2 nucleoside (or nucleotide) reverse-transcriptase inhibitors and a ritonavir-boosted protease inhibitor. Some new antiretroviral drugs under study, particularly integrase inhibitors, may prove useful in treatment-naive patients.