The study of the neural substrates underlying stress and anxiety has in recent years been enriched by a burgeoning pool of genetic information gathered from rodent studies. Two general approaches have been used to characterize the interaction of genetic and environmental factors in stress regulation: the evaluation of stress-related behavioral and endocrine responses in animals with targeted deletion or overexpression of specific genes and the evaluation of changes in central nervous system gene expression in response to environmental perturbations. We review recent studies that have used molecular biology and genetic engineering techniques such as in situ hybridization, transgenic animal, and antisense oligonucleotide gene-targeting methodologies to characterize the function of corticotropin-releasing hormone (CRH) system genes in stress. The effects of genetic manipulations of each element of the CRH system (CRH, its two receptors, and its binding protein) on stress-related responses are summarized. In addition, the effects of stress (acute, repeated, or developmental) on CRH system gene expression are described. The results from these studies indicate that experimentally engineered or stress-induced dysregulation of gene expression within the CRH system is associated with aberrant responses to environmental contingencies. These results are discussed in the context of how CRH system dysfunction might contribute to stress-related psychopathology and are presented in conjunction with clinical findings of CRH system dysregulation in psychiatric illness. Finally, future research strategies (i.e., high-throughput gene screening and novel gene-targeting methodologies) that may be used to gain a fuller understanding of how CRH system gene expression affects stress-related functioning are discussed.