Fertility in mammals is critically dependent upon episodic gonadotropin hormone secretion. Males exhibit short pulses of hormone release every 3–4 hours, while females show pulsatile release in addition to a prolonged day-long GnRH surge that occurs once a month to trigger ovulation. While it had been appreciated for decades that the gonadotropin-releasing hormone (GnRH) neurons represented the final output neuron of the hypothalamic circuitry controlling gonadotropin secretion, the mechanism through which episodic GnRH release occurred remained a mystery. The watershed discovery unravelling this mechanism arose through the identification of infertile human pedigrees with mutations in kisspeptin signalling. Investigations have subsequently identified that two different populations of kisspeptin neurons exist within the hypothalamus and that, remarkably, one represents the “pulse generator” whilst the other, found only in females, is the “surge generator”.  The detailed understanding of the kisspeptin pulse and surge generators, acquired primarily through genetic mouse models, has now provided new avenues for the beneficial regulation of fertility in humans and other species.