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Following the observation that exogenous peripheral injection of CCK could inhibit food intake, the mechanisms by which CCK influences the gut–brain pathway have been the subject of intense study for nearly 30 years. Recently, it has become evident that the system is more complex and that the consequences of CCK's action on the gut–brain pathway are more far reaching than previously recognized. This review will examine the recent evidence showing the role of CCK and CCK1Rs in modulating expression of other receptors for orexigenic and anorexigenic regulatory peptides at the level of vagal afferent neurons. In addition, new evidence showing the importance of the action of CCK at the level of the vagus nerve in the regulation of food intake, body weight, and in activation of an anti-inflammatory pathway will be reviewed.