The initiation of mammalian puberty requires an increased pulsatile release of gonadotrophin hormone releasing hormone (GnRH) from the hypothalamus. This increase is brought about by changes in transsynaptic and glialneuronal communication. Coordination of this regulatory neuronalglial network likely requires the participation of a multiplicity of genes hierarchically arranged within discrete, but interactive, networks. The identity and structural features of at least one of these hypothalamic networks has been proposed based on results obtained using high throughput, molecular and bioinformatics strategies, in combination with a system biology approach. Although the genes composing this network have diverse cellular functions, they share the common feature of having been earlier identified as involved in tumor suppression/tumor formation. A prominent member of this group is KiSS1, a gene recently shown to be essential for the occurrence of puberty in mice and humans. Cis-regulatory analysis indicated that the network contains five major hubs (CDP/CUTL1, MAF, p53, YY1, and USF2) controlling the network at the transcriptional level. These hubs are not only connected to genes encoding proteins required for intracellular signaling, and cellcell communication, but also with other upper-echelon genes (OCT2, TTF1, EAP1) involved in the transcriptional regulation of the pubertal process. The existence of functionally connected genes controlling the pubertal process is consistent with the concept that puberty is under genetic control, and that the genetic underpinnings of both normal and deranged puberty are polygenic rather than specified by a single gene. This and other networks yet to be identified may operate within the mammalian hypothalamus to facilitate and integrate cellular and cellcell communication programs required for the acquisition of female reproductive competence. Supported by NIH grants HD050798, HD25123, MH65438, U54 HD18185, and RR00163.