Stress exacerbates disease, and understanding its molecular mechanisms is crucial to the development of novel therapeutic interventions to combat stress-related disorders. The driver of the stress response in the Hypothalamic-Pituitary-Adrenal Axis (HPA) is Corticotrophin Releasing Hormone (CRH), a neuropeptide synthesized in the Paraventricular Nucleus of the Hypothalamus. Evidence supports that CRH expression is epigenetically modified at the molecular level by environmental stimuli, causing changes in the stress response. This effect is mediated by a concert of factors that translates an individual’s experience in a changing environment into alterations in gene expression. An important regulator and epigenetic modulator of CRH expression is the transcription factor Neuron Restrictive Silencing Factor (NRSF). Previously, our lab identified numerous splice variants of NRSF that are specific to humans and predictive of differential regulatory effects on targeted gene expression. The human cell line BeWo has endogenous CRH and NRSF expression providing an in vitro model system for the molecular mediation of the initiation of the stress response. Here, we show that artificially manipulating NRSF expression through siRNA technology, overexpression by plasmid vectors, and generalized pathway cAMP induction, results in differential CRH expression. Accordingly, the present research demonstrates an epigenetic regulatory pathway that modifies the response to stress in humans and creates new therapeutic avenues for a wide spectrum of stress-related illnesses.