Recently, a subset of neurons was identified in the arcuate nucleus of the hypothalamus that colocalize three neuropeptides, kisspeptin, neurokinin B, and dynorphin, each of which has been shown to play a critical role in the central control of reproduction. Growing evidence suggests that these neurons, abbreviated as the KNDy subpopulation, are strongly conserved across a range of species from rodents to humans and play a key role in the physiological regulation of GnRH neurons. KNDy cells are a major target for steroid hormones, form a reciprocally interconnected network, and have direct projections to GnRH cell bodies and terminals, features that position them well to convey steroid feedback control to GnRH neurons and potentially serve as a component of the GnRH pulse generator. In addition, recent work suggests that alterations in KNDy cell peptides may underlie neuroendocrine defects seen in clinical reproductive disorders such as polycystic ovarian syndrome. Taken together, this evidence suggests a key role for the KNDy subpopulation as a focal point in the control of reproductive function in health and disease.