The hypothalamic-pituitary-gonadal (HPG) axis controls puberty and reproduction and is tightly regulated by a complex network of excitatory and inhibitory neuroendocrine factors. Delayed or absent activation of the HPG axis results in delayed puberty or hypogonadotropic hypogonadism, whereas early activation results in central precocious puberty (CPP). In recent years, many genes have been identified in this complex network from genetic studies of human subjects with pubertal disorders, providing insights into the regulation of GnRH secretion and into disorders of reproduction and fertility. These new insights were heralded by the discovery of the kisspeptin system as a critical component for the activation of GnRH secretion, and followed by the discovery of the tachykinin, neurokinin B, and its role in puberty initiation, in turn, through regulation of kisspeptin secretion. More recently, we identified loss-of-function mutations in the maternally imprinted MKRN3 gene, encoding makorin ring finger protein 3, as an important cause of CPP. Mkrn3 is expressed at high levels in the mouse hypothalamus prepubertally and decreases prior to puberty onset, suggesting a role as a brake or inhibitor of GnRH secretion and hence of puberty. Studies in cellular and animal models will help to elucidate the mechanisms by which MKRN3 regulates GnRH secretion and provide new insights into reproductive physiology.