Purpose The symptom most frequently associated with sickle cell disease (SCD) is pain, but recent research is beginning to indicate that fatigue as an increasingly important symptom of this disease upon which to focus research efforts. This article explores biological and behavioral factors that can potentially contribute to fatigue in SCD. Organizing Framework A biobehavioral framework guides this discussion of factors that may contribute to SCD fatigue. Findings The pathophysiology of the disease process, such as the profound hemolytic anemia and unpredictable vasoocclusive crises, suggests that individuals with SCD are at risk for both acute and chronic fatigue. For example, hypoxemia can cause muscle weakness and produce oxidative stress, which, in turn, increases fatigue. Sickled erythrocytes disrupt the vascular endothelium and stimulate proinflammatory cytokines, which are linked to sleep disruptions. Pain, the most notorious symptom of SCD, has a complex and mechanistically poorly understood relationship with fatigue. Conclusions Little is known about the symptom of fatigue in SCD. Considering the biological and behavioral factors of SCD that could potentially contribute to fatigue, there is a great need for research on the nature and potential mechanisms of fatigue in SCD. Clinical Relevance Fatigue in SCD may negatively affect quality of life. Understanding factors that may contribute to fatigue aids the clinician in identifying causes and determining treatment.