Much has been learned in recent years about the central mechanisms controlling the initiation of mammalian puberty. It is now clear that this process requires the interactive participation of several genes. Using a combination of high throughput, molecular, and bioinformatics strategies, in combination with a system biology approach, we singled out from the hypothalamus of nonhuman primates and rats a group of related genes whose expression increases at the time of female puberty. Although these genes [henceforth termed tumor-related genes (TRGs)] 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. Cis-regulatory analysis revealed the presence of a hierarchically arranged gene set containing five major hubs (CDP/CUTL1, MAF, p53, YY1, and USF2) controlling the network at the transcriptional level. In turn, these hubs are heavily connected to non-TRGs involved in the transcriptional regulation of the pubertal process. TRGs may be expressed in the mammalian hypothalamus as components of a regulatory gene network that facilitates and integrates cellular and cell-cell communication programs required for the acquisition of female reproductive competence.