As medical advances improve survival, reduce disease-related morbidity, and improve quality of life, reproductive issues will take higher priority in the sickle cell disease (SCD) community. A wide variety of topics are addressed in this chapter, including fertility, gonadal failure, erectile dysfunction, and menstrual issues in SCD. Etiologies of impaired male fertility are multifactorial and include hypogonadism, erectile dysfunction, sperm abnormalities, and complications of medical therapies. Much less is known about the prevalence and etiology of infertility in women with SCD. Other reproductive issues in women included in this review are pain and the menstrual cycle, contraception, and preconception counseling. Finally, long-term therapies for SCD and their impact on fertility are presented. Transfusional iron overload and gonadal failure are addressed, followed by options for fertility preservation after stem cell transplantation. Focus is placed on hydroxyurea therapy given its benefits and increasing use in SCD. The impact of this agent on spermatogenesis, azoospermia, and the developing fetus is discussed.