First-line antiretroviral regimens are safe, effective and easily administered (one pill taken once daily). Even so, the annual failure rate is around 10-15% of treated patients. Second-line regimens have a number of limitations, disproportionately impacting resource-limited settings. Ideally choice of the second-line regimen is guided by expensive and technically demanding HIV drug resistance testing. Drug resistance, previous treatment and known toxicities means individuals require a tailored regimen of second-line therapy where multiple pills are taken more than once a day. Unaddressed, the challenge of care for patients failing first-line antiretroviral therapy could profoundly and negatively affect the long-term effectiveness of treatment programs for infected individuals and their communities.