Sickle cell disease (SCD) research and clinical care have traditionally focused on physical comorbidities and complications. Mental health has received less attention until recently. We now recognize that patients with SCD are at increased risk for mental health disorders, which significantly impact disease outcomes and quality of life. Thus, ignoring mental health will contribute to worse disease outcomes and complications throughout these patients’ lives, thereby perpetuating the health disparities faced by this population. It is therefore critical to diagnose and address mental health disorders and symptoms; however, patients are not routinely assessed for mental health symptoms when seeking SCD care. To address this gap, there has been an increase in studies aimed at understanding the prevalence of mental health disorders, clinical presentation, and the full extent of the impact on outcomes in SCD. This chapter presents an overview of the most common psychological symptoms and mental health disorders affecting children and adults with SCD, factors influencing their mental health and quality of life, and the long-term consequences of untreated mental health comorbidities. It also identifies gaps in research and practice, and emphasizes that assessment of mental health is a necessary part of routine treatment for SCD.