Atazanavir (Reyataz®) is a protease inhibitor (PI) for the treatment of HIV infection. Several trials have demonstrated the good efficacy and toxicity profile of atazanavir boosted by ritonavir (atazanavir/r). However, several toxicity events and pharmacokinetic issues due to drug-to-drug interactions (partly related to ritonavir) may complicate atazanavir/r therapy. This is why regimens with unboosted atazanavir have been experimented with and are used in clinical practice. The aim of this article is to identify the clinical settings in which unboosted atazanavir may be a safe and effective option for the long-term control of HIV replication. Despite the fact that a favourable lipid profile and good gastrointestinal tolerability have been reported in comparative trials, unboosted atazanavir should not be considered an optimal choice for treatment-naive patients. In fact, boosting with ritonavir produces higher atazanavir plasma levels, which are beneficial in terms of efficacy, especially in untreated patients with high plasma HIV RNA. Clinical data indicate that, in patients with sustained undetectable HIV RNA and without previous virological failure or HIV drug resistance-associated mutations, a switch to unboosted atazanavir-based regimens is a feasible option to control and prevent toxicity events, especially in patients who cannot tolerate ritonavir and in those with severe hyperbilirubinaemia on atazanavir/r. Moreover, while unboosted atazanavir must not be used in pregnant women, it is a recommended option in special populations, such as patients with moderate liver insufficiency. Lastly, unboosted atazanavir in combination with raltegravir may allow the construction of a well tolerated and effective regimen without nucleoside reverse transcriptase inhibitors in patients for whom these drugs are contraindicated. In conclusion, there is a good rationale, significant clinical interest and accumulating clinical experience with unboosted atazanavir-based regimens, although this formulation should be used only in specific situations and as a maintenance strategy. Moreover, therapeutic drug monitoring could be useful in specific circumstances (such as in patients with liver impairment or in case of potential drug-drug interactions).