The production and commercial use of novel man-made chemicals over the past century have introduced a variety of industrial compounds into the environment, including polychlorinated biphenyls (PCBs). PCBs alter a multitude of physiological processes in humans and wildlife, and our laboratory and others have been studying the endocrine-disrupting mechanisms by which PCBs specifically affect the hypothalamic control of reproduction. This article will review the literature on PCB effects on reproductive neuroendocine systems, focusing on effects of exposure during fetal development, a life stage that is particularly susceptible to endocrine disruption. We also provide the example of how the use of a whole genome microarray (Affymetrix rat 2.0) to assay gene expression in the preoptic area (POA; a part of the hypothalamus involved in the control of reproductive physiology and behavior) of female rats fetally exposed to PCBs enabled us to determine whether there was wholesale reprogramming of genes in a manner maintained in adulthood. We also use this method to interrogate the pathways by which PCBs exert these effects, and to ascertain any commonalities of potential dose-response relationships, as endocrine-disrupting chemicals (EDCs) often exert non-traditional, non-monotonic effects on physiological systems. The results show that there are indeed a large number of POA genes and pathways perturbed by prenatal PCB exposure. Although some predicted estrogenic pathways were identified by this method, we also identified other hormonal, neurotransmitter, immune, blood, transcriptional, and intracellular signaling pathways that were affected by the prenatal PCBs. Furthermore, this analysis enabled us to show that the dose-response relationships between exposure and gene expression were almost entirely non-monotonic, with U-shaped and inverted U-shaped the most common. The example of PCBs as neuroendocrine disruptors may predict the effects of many other compounds, including anthropogenic chemicals used today such as bisphenol A and phthalates.