PURPOSE OF REVIEW: The use of protease inhibitors in resource-limited settings will increase in coming years as HIV treatment cohorts mature. We review data available to guide the expanded use of protease inhibitors in these settings. RECENT FINDINGS: The safety and effectiveness of protease inhibitors may be affected by the context of their use, yet limited data exist regarding the use of these agents in resource-limited settings in either first or subsequent regimens. Critically, data are needed regarding optimal regimens at time of first-line nonnucleoside reverse transcriptase inhibitor-based regimen failure. A number of alternative strategies are being investigated, including dual-boosting, monotherapy and dose reduction. Despite recent progress cost, storage requirements, drug interactions and formulation continue to hinder the use of protease inhibitors, particularly for children. SUMMARY: Protease inhibitors are the core component of second-line therapy in resource-limited settings and are used in specific situations in first-line therapy. Use of second-line regimens has been more diverse than first line, but WHO has recently prioritized regimens containing lopinavir/ritonavir or ritonavir-boosted atazanavir. As use of protease inhibitors in resource-limited settings increases evidence needs to be accrued to guide further expanded use.