While past research suggests that ghrelin stimulates appetite through an action on hypothalamic signaling, recent evidence indicates that the peptide acts via mesotelencephalic dopamine neurons to alter appetitive motivation. In the present study, rats were trained to operantly respond for food on a progressive ratio PR5 schedule until stable breakpoints were established. Ghrelin (30–300 pmol) was then injected directly into the ventral tegmental area (VTA) and the 300 pmol dose was observed to increase breakpoint. The dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA, 6 μg) was subsequently administered into the VTA resulting in a significant depletion of striatal dopamine. Stable breakpoints were then re-established. When ghrelin's effects were reassessed, the peptide's ability to alter operant responding for food was reliably reduced. Our findings demonstrate that ghrelin induces food-reinforced behavior in the mesotelencephalic reward pathway and that this effect is dependent on intact dopaminergic signaling. We conclude that the metabolic peptide ghrelin interacts with dopamine, within reward circuitry, to modulate appetitive behavior.