Infertility affects approximately 1 in 10 couples. Causes include physical, environmental, and genetic factors, and both partners are equally likely to be affected. It is often difficult to establish a diagnosis for the cause of infertility.“Idiopathic infertility” still predominates as a diagnosis, which reflects the challenges of defining the pathophysiology of infertility in individual couples. Nevertheless, treatment is often successful, using ovulation induction, in vitro fertilization, or ICSI (intracytoplasmic sperm injection). Given the large number of genes that are potentially involved in sex determination, steroidogenesis, and fertility, space limitations preclude a comprehensive review of all genetic abnormalities associated with infertility (eg. chromosomal abnormalities, disorders of steroid biosynthesis, and metabolic disorders). In this review, we have focused primarily on genes involved in the hypothalamic-pituitary-gonadal (HPG) axis. These disorders have provided important insight into the function of the reproductive axis in humans and may point the way toward improved strategies for the diagnosis and treatment of infertility. Several single-gene disorders affect HPG function and fertility in humans (Fig. 1 and Table 1). Although most of these disorders are relatively rare, they should be considered as causes of infertility for a variety of reasons. First, understanding the pathophysiology of infertility can allow patients to be counseled about their prognosis and the risk of transmitting a condition to their children. Second, treatment can be tailored more appropriately in the context of known hormonal deficits. Finally, it is likely that the cases described to date represent the most severe end of the phenotypic spectrum. Disorders associated with milder phenotypes may be more common and could provide further information about the transcription factors, hormones, and receptors involved in reproduction.