Human reproduction and fertility are completely dependent upon the neuroendocrine control of the hypothalamus-pituitary-gonadal (HPG) axis and its hierarchy of secreted hormones. The human reproductive system is controlled by the hypothalamus through the decapeptide gonadotropin-releasing hormone (GnRH), which displays a remarkable conservation over millions of years of evolution across different species. The secretion of GnRH depends on less than 4000 GnRH-secreting neurons, which have an extracranial origin and finally migrate into the hypothalamic preoptic area. As of the tenth week of gestation, these neurons start secreting GnRH until the first 4–6 months of life, when GnRH secretion is “switched-off” until pubertal onset. At puberty, the secretion of GnRH is switched back “on” with a characteristic pulsatile manner that is maintained during adulthood. The regulation of GnRH-secreting neuron activity throughout the lifespan is not completely understood, but it is clearly the result of a sophisticated network of stimulatory and inhibitory inputs, which include different subgroups of neurons afferent to GnRH-secreting neurons centrally and the gonadal steroid feedback peripherally. The present chapter of this Textbook will focus on the ontogeny of GnRH-secreting neurons and the mechanisms so far known implicated in the regulation of their neurosecretory activity.