This review summarizes experimental and clinical data in support of the hypothesis that the known risk factors for Pancreatic Ductal Adenocarcinoma (PDAC), smoking, psychological stress, alcohol consumption, diabetes and pancreatitis-, create hyperactivity of the neurotransmitters norepinephrine and epinephrine in the pancreas. Smoking, psychological stress and alcohol sensitize the nicotinic acetylcholine receptors (nAChRs) that regulate the synthesis and release of PDAC stimulating stress neurotransmitters norepinephrine and epinephrine by nerves of the symapthicus, the adrenal gland and by pancreatic cancer cells and their epithelial precursor cells while simultaneously desensitizing the nAChRs that govern the synthesis and release of the PDAC inhibiting neurotransmitter g-aminobutyric acid (GABA). Experimental data generated in vitro and in animal models emphasize a key role of Gs-coupled β-adrenergic and PGE2 receptors in the activation of multiple signaling pathways by stress neurotransmitters in PDAC. The clinical behavior of PDAC confirms that sympathetic nerves that release stress neurotransmitters are important mediators of PDAC progression. Emerging experimental evidence suggests that lessons learned from the long-term management of cardiovascular disease, which is governed by sympathicus hyperactivity, can be successfully utilized to improve survival rates of PDAC patients and to prevent the development of PDAC in individuals at risk.