Finding a widely available cure for sickle cell anemia (HbSS) still remains a challenge one hundred years after its discovery as a genetically inherited disease. However, growing interest in the nutritional problems of the disease has created a body of literature from researchers seeking nutritional alternatives as a means of decreasing morbidity and improving quality of life among HbSS patients. This review demonstrates that over the past 30 years the role of protein/energy deficiency in HbSS has been more clearly defined via direct measurements, leading to the concept of a relative shortage of nutrients for growth and development, despite apparently adequate dietary intakes. Although there is still a paucity of data supporting the efficacy of macronutrient supplementation, it is becoming clearer that recommended dietary allowances (RDAs) for the general population are insufficient for the sickle cell patient. A similar shortage is likely to be true for micronutrient deficiencies, including recent findings of vitamin D deficiency that may be associated with incomplete ossification and bone disease, which are well known complications of HbSS disease. We conclude that there is need for more effort and resources to be dedicated to research (including supplementation studies of larger sample size) aimed at establishing specific RDAs for HbSS patients, much like the specific RDAs developed for pregnancy and growth within the general population.