Mounting clinical and experimental evidence supports the causal association between paternal preconception environment and dysregulation of offspring development and health outcomes. Our research has identified a potential mechanism linking these phenomena in terms of the generation of epigenetic stress signals (i.e. small non-coding RNAs; sncRNA), which are delivered to spermatozoa during their transit through the male reproductive tract (epididymis). Our work has alluded to the possibility that the production of such sncRNAs is regulated by stress-responsive transcription factors (TFs), and their associated gene regulatory networks, within the epididymal tissue. As a first step toward validating this hypothesis, we performed a comprehensive in-silico analysis of publicly available data (transcriptomic and proteomic) to identify expression of TFs in the human and mouse epididymis. This analysis was intended to not only provide a deeper understanding of epididymal biology but also shed light on how this tissue senses and responds to stressors. Our analysis enabled the curation of a core epididymal inventory of 2,004 (human) and 733 (mouse) TFs, in which the majority (i.e., human: 87%, mouse: 80%) were found to be expressed across all regions of the epididymis. Moreover, by assessing data from in-vivo and in-vitro stress exposure models, we were able to identify several TFs [including: high-mobility group AT-hook 2 (HMGA2), glucocorticoid receptor (NR3C1), and pre-B-cell leukemia transcription factor 1 (PBX1)], whose expression was significantly altered (p<0.05, FC ±2) under the imposed exposure regimens (e.g., acrylamide). Notably, a subset of these TFs have been implicated in phenotypes impacting reproduction and developmental processes, as well as regulating expression profiles of sncRNAs linked with adverse neurological, developmental, and reproductive diseases in offspring. Future research will focus on confirming the chain of cause-and-effect linking these epididymal TFs to the propagation of sncRNAs delivered to maturing sperm cells and thereafter influence embryo development and offspring health.