Evidence demonstrates that scale-up of HIV services has produced stronger health systems and, conversely, that stronger health systems were critical to the success of the HIV scale-up. Increased access to and effectiveness of HIV treatment and care programs, attention to long-term sustainability, and recognition of the importance of national governance, and country ownership of HIV programs have resulted in an increased focus on structures that compromise the broader health system. Based on a review published literature and expert opinion, the article proposes 4 key health systems strengthening issues as a means to promote sustainability and country ownership of President's Emergency Plan for AIDS Relief and other global health initiatives. First, development partners need provide capacity building support and to recognize and align resources with national government health strategies and operational plans. Second, investments in human capital, particularly human resources for health, need to be guided by national institutions and supported to ensure the training and retention of skilled, qualified, and relevant health care providers. Third, a range of financing strategies, both new resources and improved efficiencies, need to be pursued as a means to create more fiscal space to ensure sustainable and self-reliant systems. Finally, service delivery models must adjust to recent advancements in areas of HIV prevention and treatment and aim to establish evidence-based delivery models to reduce HIV transmission rates and the overall burden of disease. The article concludes that there needs to be ongoing efforts to identify and implement strategic health systems strengthening interventions and address the inherent tension and debate over investments in health systems.