New treatment modalities for HIV infection in 2005 are based on the availability of new antiretrovirals and new strategies for their use. For reverse transcriptase inhibitors, abacavir/lamivudine and tenofovir/emtricitabine combinations minimize risks of mitochondrial toxicity and are now available as a single daily tablet. New protease inhibitors (PI) are boosted by ritonavir. Some that are already available (atazanavir, fosamprenavir) have good tolerance, resistance and dosing profiles. PIs in advanced stages of development (tipranavir and TMC114) specifically target strains with resistant mutations. Entry inhibitors affecting the CCR5 co-receptor are a new promising drug class. Enfuvirtide, a fusion inhibitor administered in subcutaneous injections, significantly improves the antiretroviral and immunologic response to antiretroviral regimens in patients with previous treatment failures. For successfully treated patients, simplification and treatment interruptions are sometimes possible. For non-responders, thorough virological-pharmacological assessment is necessary, together with access to new molecules and new drug classes.