Sickle cell disease (SCD), a rare genetic disorder, significantly influences patients’ psychological and emotional well-being. Those with SCD face an increased risk of developing psychological and behavioral symptoms of mental health disorders, due to the disease itself as well complex biological, psychological, and social factors. There is increased interest in framing these factors within a biopsychosocial model for health to better understand their interaction and how they impact mental health. Causal pathways are not always clear, as SCD-related pathology may contribute to disparities in psychosocial resources, which in turn affect both mental and physical health outcomes, becoming a vicious cycle. This chapter presents an overview of environmental, biological, and psychosocial factors that are either known risks to mental health or are emerging areas of interest. The chapter concludes with recommendations for future research into behavioral health treatments for mental health issues in this population.