This article explores the role of kisspeptin in stimulating gonadotropin-releasing hormone (GnRH) release through the G protein-coupled receptor 54 (GPR54). The study shows that GPR54 is expressed in GnRH neurons in the mouse hypothalamus, suggesting that kisspeptin, the ligand for GPR54, acts directly on these neurons. The research also demonstrates that in gpr54−/− mice, which lack functional GPR54, kisspeptin injections do not stimulate LH and FSH release, indicating that kisspeptin's effect on gonadotropin release is dependent on GPR54 signaling. Additionally, when administered intracerebroventricularly in sheep, kisspeptin causes a dramatic release of GnRH into the cerebrospinal fluid, with a parallel rise in serum LH, demonstrating that kisspeptin directly stimulates GnRH release at the level of GnRH neurons. These findings suggest that GPR54 is a key control point in the hypothalamic-pituitary-gonadal axis, and kisspeptin functions as a neurohormonal effector. The study also highlights the importance of GPR54 in the regulation of GnRH release, as the absence of GPR54 leads to hypogonadism without affecting the migration or morphology of GnRH neurons. The results support the idea that GPR54 is essential for the normal development of puberty and that kisspeptin acts through GPR54 to stimulate GnRH release, which is crucial for reproductive function. The study provides important insights into the molecular mechanisms underlying the regulation of the reproductive axis and has implications for the diagnosis and treatment of reproductive disorders.This article explores the role of kisspeptin in stimulating gonadotropin-releasing hormone (GnRH) release through the G protein-coupled receptor 54 (GPR54). The study shows that GPR54 is expressed in GnRH neurons in the mouse hypothalamus, suggesting that kisspeptin, the ligand for GPR54, acts directly on these neurons. The research also demonstrates that in gpr54−/− mice, which lack functional GPR54, kisspeptin injections do not stimulate LH and FSH release, indicating that kisspeptin's effect on gonadotropin release is dependent on GPR54 signaling. Additionally, when administered intracerebroventricularly in sheep, kisspeptin causes a dramatic release of GnRH into the cerebrospinal fluid, with a parallel rise in serum LH, demonstrating that kisspeptin directly stimulates GnRH release at the level of GnRH neurons. These findings suggest that GPR54 is a key control point in the hypothalamic-pituitary-gonadal axis, and kisspeptin functions as a neurohormonal effector. The study also highlights the importance of GPR54 in the regulation of GnRH release, as the absence of GPR54 leads to hypogonadism without affecting the migration or morphology of GnRH neurons. The results support the idea that GPR54 is essential for the normal development of puberty and that kisspeptin acts through GPR54 to stimulate GnRH release, which is crucial for reproductive function. The study provides important insights into the molecular mechanisms underlying the regulation of the reproductive axis and has implications for the diagnosis and treatment of reproductive disorders.