To regulate reproduction in mammals, internal and external status is communicated to the hypothalamic-pituitary-gonadal axis via a coordinated balance of stimulatory and inhibitory neurochemical systems. This review describes the neuroanatomical organization of the kisspeptin system in the hypothalamus, and summarizes its role in signaling hypothalamic GnRH neurons, namely: multimodal actions of kisspeptin in the control of GnRH secretion during different physiological states of animals; involvement of kisspeptin in relaying metabolic information to hypothalamic GnRH neurons; neurobiological mechanisms underlying kisspeptin activation of GnRH neurons during puberty onset; effect of gonadal steroids in the early postnatal period in rodents on kisspeptin expression in the hypothalamus and gonadotropin secretion in adults; effect of photoperiod and metabolic cues on the activation/inhibition of hypothalamic-pituitary-gonadal axis in seasonally breeding species by kisspeptin.