HIV/AIDS, tuberculosis, and malaria are 3 major global public health threats and cause substantial morbidity, mortality, negative socioeconomic impact, and human suffering. Despite the significant increase in financial support and recent progress in addressing these 3 diseases, important obstacles and unmet priorities remain. Disease-specific interventions have had a considerable impact on improving health systems. However, despite considerable investment, weak health systems, inadequate human resources, and poor laboratory infrastructure continue to be major obstacles to expanding health services. Health system strengthening should be addressed in an integrated approach that includes HIV-, tuberculosis-, and malaria-specific interventions. Investment in strategic information and public health laboratory network capacity strengthening are key actions to expand services to successfully address those diseases in heavily impacted countries.