Pancreatic ductal adenocarcinoma (PDAC) has a near 100% mortality because it is generally detected at an advanced stage and responds poorly to existing therapeutics. This review summarizes current evidence suggesting important roles of neurotransmitter receptors in the regulation of this malignancy. Experimental evidence indicates that the alpha(7)-nicotinic acetylcholine receptor (alpha(7)nAChR) stimulates PDAC via stress neurotransmitter-mediated activation of beta-adrenergic signaling while the alpha(4)beta(2)nAChR inhibits PDAC via GABA-mediated inhibition of adenylyl cyclase activation. In analogy to molecular mechanisms that govern nicotine addiction, chronic exposure to nicotine or its nitrosated derivative nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone render the stimulatory alpha(7)nAChR hyperactive while desensitizing the inhibitory alpha(4)beta(2)nAChR. Accordingly, PDAC intervention strategies should include the diagnosis of unphysiological neurotransmitter levels and aim to restore any imbalance in stimulatory and inhibitory neurotransmitters.