Demonstrating marked variability across the life cycle, yet exquisitely regulated, the hypothalamic secretion of GnRH in the human triggers a cascade of events leading to gonadal sex steroid secretion, folliculogenesis, and spermatogenesis. Animal studies have demonstrated a remarkable concordance between GnRH pulses in hypothalamic portal blood and LH pulses in the periphery (1), establishing that LH pulsatility is a reflection of antecedent, intermittent discharges of GnRH. Not only is pulsatile GnRH secretion necessary for the maintenance of normal gonadotropin secretion, but continuous, as opposed to pulsatile, administration of GnRH actually desensitizes gonadotropin release (2). In GnRH-deficient animals and humans, administration of pulsatile GnRH reestablishes normal hormone responses, and in patients with congenital hypogonadotropic hypogonadism, pulsatile GnRH can recapitulate normal pubertal development (2–5). Although these principles of GnRH secretion have been established for over two decades, the regulation of GnRH secretion via sex steroid and nonsteroidal factors in normal reproduction (ie the menstrual cycle), different stages of the life cycle (ie gonadotropin amplification during puberty) and pathophysiologic states (ie polycystic ovary syndrome) is a complicated and incompletely understood phenomenon. Patients with single gene mutations within the hypothalamic-pituitary-gonadal axis have provided unique avenues to increase our understanding of reproductive neuroendocrinology. Genetically engineered animal models have further elucidated the roles of specific hormones in reproductive function, by confirming and extending human findings, establishing species-specific phenotypes, or predicting phenotypes when no human model exists. The combination of both animal and human tools has proven to be powerful, revealing paradoxes of reproductive biology and unexpected differences between species. For example, over 20 yr ago, a naturally occurring mouse model of hypogonadotropic hypogonadism (hpg mouse) was described with low levels of LH and FSH, sexual immaturity, and infertility (6). The hypogonadism was due to a deletional mutation encompassing the distal half of the gene encoding GnRH and the GnRH-associated peptide (GAP)(7); mice homozygous for this mutation had arrested germ cell development but reproductive function could be restored with gene therapy (8). However, despite the obvious candidacy of GnRH as a cause of hereditary hypogonadism in the human, no mutations within the GnRH gene have yet been discovered in this population (9–11). Therefore, spontaneously occurring mutations in humans and animals as well as targeted disruption of selected genes must be evaluated in a complementary fashion. Examples of some of these mutations, their genotype/phenotype correlations, and the reproductive paradoxes they present, are discussed below.