A theoretical biopsychosocial framework for SCD that illustrates the cyclical physiological and behavioral pathways through which psychosocial stressors influence SCD morbidities. This framework is intended to guide research on the bidirectional mechanisms linking stressors, stress responses, and health outcomes. Physiological pathways: when the brain perceives a stressor, physiological stress-related biomarkers (glucocorticoids, catecholamines, and cytokines) are released to repond to the stressor and gain allostasis. Experiences with chronic and recurrent acute psychosocial stressors can result in dysregulated diurnal stress response patterns and elevated systemic inflammation. Inflammatory outcomes can then lead to increased hemolysis and SCD morbidities. Conversely, anemic conditions and systemic ischemia associated with SCD morbidities could theoretically result in further dysregulation of the stress response system via pathophysiological mechanisms. Behavioral pathways: experiences with chronic and recurrent acute psychosocial stressors and dysregulated stress response biomarkers can also result in depressed mood and withdrawn behaviors, resulting in disengagement in care and increased SCD morbidities. Conversely, elevated SCD morbidities are associated with increased disease-related stressors such as school or work absences, peer or family conflict, and health care bias, which can further result in dysregulated stress responses.