Protease inhibitors (PIs) have created a new future for many HIV-infected patients. After the initial enthusiasm following its first approval, complex drug schedules and frequent toxicities of PIs prompted researchers to find alternative drugs. However, it is now clear that not all triple combinations are equally valid. Certain regimens based on the association of only reverse transcriptase inhibitors have shown high rates of virological failure, with the selection of cross-resistance mutations. The availability of new generation PIs, such as atazanavir, with improved safety profiles and more convenient administration schedules returns this drug family to the front of the HIV therapeutic armamentarium. Recent clinical studies support the assertion that atazanavir may display excellent behavior as part of first-line regimens in rescue interventions or in simplification strategies.