The hypothalamic-pituitary-gonadal (HPG) axis controls puberty and reproduction and is tightly regulated by a complex network of excitatory and inhibitory 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, providing insight into the regulation of GnRH secretion. These advances 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 pubertal activation in turn, through regulation of kisspeptin secretion. More recently, we identified loss-of-function mutations in the MKRN3 gene, encoding makorin ring finger protein 3, as an important cause of CPP. MKRN3 is an imprinted gene on chromosome 15q11.2 in the Prader-Willi Syndrome critical region, with expression only from the paternally inherited allele. MKRN3 is expressed at high levels in the mouse hypothalamus prepubertally and decreases prior to puberty onset, suggesting that it acts as a “brake” on GnRH secretion. To date, MKRN3 is the first factor to be identified that likely has an inhibitory role on puberty in humans. The discovery of this new genetic link to early puberty will help to diagnose the cause of precocious puberty or to identify children at risk for developing precocious puberty, and the elucidation of the mechanisms by which MKRN3 regulates GnRH secretion, will bring new insights into reproductive physiology.