During the past 20 years, remarkable advances have been made regarding the molecular basis of many disorders affecting reproduction. This is particularly true for patients who present with delayed puberty due to GnRH deficiency. These affected males and females manifest low serum levels of sex steroids, low or normal gonadotropins, and no other pituitary pathology. The pathophysiology of GnRH deficiency is complex, but 2 major phenotypes are observed. When hypothalamic GnRH gene regulation or GnRH synthesis, secretion, or signaling is impaired, the resulting phenotype is normosmic hypogonadotropic hypogonadism (nHH). However, it is also known that GnRH neurons originate outside of the brain and migrate along with olfactory neurons from the nasal region into the hypothalamus. If this migratory pathway of GnRH and olfactory neurons is disrupted, anosmia accompanies hypogonadotropic hypogonadism, known as Kallmann syndrome (KS). KAL1, the first gene for KS, was identified more than 20 yearsagoinaffectedmaleswithX-linkedrecessiveKS. Valuable families with Xp deletions and chromosomal translocations permittedthelocalizationofthisgeneonchromosomeXp22. 32 (1, 2). Confirmation that KAL1 mutations cause KS was obtained by the demonstration of intragenic deletions and point mutationssegregatingwithinfamilies, whichwereabsentinunaffected controls (3, 4). About 7 years later, mutations in GNRHR (GnRH receptor) were identified in nHH patients (5, 6). TheGNRHRgene was the first gene in which mutations were found to cause nHH and autosomal recessive disease. Therefore, GNRHR was the first causative gene identified to be involved in GnRH deficiency in women (5, 6). Since that time, mutations in at least 16 other genes and 6 more causing combined pituitary hormone deficiency have been identified to cause nHH and KS in autosomal dominant, autosomal recessive, and X-linked recessive inheritance patterns (7). Mutations in 2 (digenic) or more (oligogenic) genes have been reported in a small percentage of KS and nHH patients (8, 9). In addition, a variety of associated nonreproductive anomalies may be seen in KS patients such as unilateral renal agenesis, midline facial defects, dental agenesis, skeletal abnormalities, neurological abnormalities such as synkinesia, ataxia, or visual symptoms, deafness, and cardiac anomalies (7). Mutations in some genes seem to cause just KS (KAL1) or just nHH (such as ligand/receptor pairs GNRH1/GNRHR, LEP/LEPR, KISS1/KISS1R, and TACR3/TAC3; and rarely NR0B1 or PCSK1), whereas some may cause either nHH or KS (FGFR1, FGF8, CHD7,