Vagal afferents regulate energy balance by providing a link between the brain and postprandial signals originating from the gut. In the current study, we investigated melanocortin‐4 receptor (MC4R) expression in the nodose ganglion, where the cell bodies of vagal sensory afferents reside. By using a line of mice expressing green fluorescent protein (GFP) under the control of the MC4R promoter, we found GFP expression in approximately one‐third of nodose ganglion neurons. By using immunohistochemistry combined with in situ hybridization, we also demonstrated that ∼20% of GFP‐positive neurons coexpressed cholecystokinin receptor A. In addition, we found that the GFP is transported to peripheral tissues by both vagal sensory afferents and motor efferents, which allowed us to assess the sites innervated by MC4R‐GFP neurons. GFP‐positive efferents that co‐expressed choline acetyltransferase specifically terminated in the hepatic artery and the myenteric plexus of the stomach and duodenum. In contrast, GFP‐positive afferents that did not express cholinergic or sympathetic markers terminated in the submucosal plexus and mucosa of the duodenum. Retrograde tracing experiments confirmed the innervation of the duodenum by GFP‐positive neurons located in the nodose ganglion. Our findings support the hypothesis that MC4R signaling in vagal afferents may modulate the activity of fibers sensitive to satiety signals such as cholecystokinin, and that MC4R signaling in vagal efferents may contribute to the control of the liver and gastrointestinal tract. J. Comp. Neurol. 518:6–24, 2010. © 2009 Wiley‐Liss, Inc.