Sickle cell anemia (SCA) is a genetic disease that affects mostly individuals of African and/or Hispanic descent, with the majority of cases in sub-Saharan Africa. Individuals with this disease show slowed growth, delayed sexual maturity, and poor immunologic function. These complications could partly be explained by the state of undernutrition associated with the disease. Proposed mechanism of undernutrition include protein hypermetabolism, decreased dietary intake possibly from interleukin-6-related appetite suppression, increased cardiac energy demand/expenditure, and increased red cell turnover. All the above mechanisms manifest as increased resting energy expenditure. Nutritional intervention utilizing single or multiple nutrient supplementation has led to improved clinical outcome, growth, and sexual maturation. Studies are currently underway to determine the best possible approach to applying nutritional intervention in the management of SCA. Management of SCA will, of necessity, involve a nutritional component, given the sociodemographic distribution of those most affected by the disease, the ease of a nutritional approach, and the wider reach that such an approach will embody.