Although the availability of antiretroviral therapy has increased rapidly to reach over three million people in low- and middle-income countries, coverage remains low as only 31% of people in need were receiving antiretroviral therapy in sub-Saharan Africa. Antiretroviral therapy scale-up needs to continue to grow exponentially to meet the need for universal access and keep pace with or exceed the new HIV infections. This calls for strategies that will have the greatest impact on the reduction of opportunistic infections, toxicities, and early mortality after antiretroviral therapy initiation as well improve adherence, clinical, immunological, and virologic responses, patient retention in antiretroviral therapy programs, and overall quality of life of people living with HIV/AIDS. Expanding antiretroviral therapy to all those eligible requires evidence-based decisions about how, when, and where expansion should occur. In this article we highlight some of the strategies that have optimized HIV treatment outcomes within the constraints of limited resources in sub-Saharan Africa. Key strategies to optimize HIV treatment outcomes include, i) scaling up HIV testing to identify all in need of HIV treatment, ii) strengthening the links between HIV diagnosis and comprehensive HIV/AIDS care, iii) timely initiation of antiretroviral therapy, iv) optimal diagnosis and treatment of opportunistic infections and comorbidities, v) investing in laboratory tests to support clinical monitoring of patients on antiretroviral therapy, vi) maximizing adherence to antiretroviral medication and retention of patients in HIV/AIDS care, viii) improving the health infrastructure, and increasing the human resources to handle the growing numbers of people in need of HIV treatment.