Survival has been greatly enhanced with the adequate and effective treatment of HIV infection. Surviving and surviving well are important pieces of the disease management puzzle. Nutritional well-being has been closely associated with both survival and quality of life in HIV and other diseases. The effects and interactions of currently used antiretroviral therapies can compromise nutritional well-being. The challenges posed to researchers, clinicians, and patients in evaluating and treating nutrition-related effects of life-saving antiretroviral medications affect health care goals, recommendations, and decisions. Challenges include identifying emerging problems, prioritizing clinical problems, expediting the implementation of clinical trials, developing research-based interventions that are realistic and usable in practice, decreasing the time lag to incorporate research findings into practice, and developing or adapting evidence-based clinical guidelines. This article will explore these challenges, offer thought-provoking questions in the development of research and clinically viable solutions, and propose future directions for management strategies of antiretroviral-related problems.