Neuropeptides and peptide hormones are the most diverse messenger molecules in animals and play important roles in the regulation of daily physiology and a multitude of behaviors. Many of these peptides and their cognate receptors are structurally and functionally conserved over evolution in bilaterians. Prime examples of this are peptides related to cholecystokinin (CCK) and gastrin. Here, we discuss CCK signaling in mammals and several key vertebrate groups, as well as in invertebrates. In mammals, CCK is primarily produced by intestinal endocrine cells and brain neurons and regulates gall bladder contractions, pancreatic enzyme secretion, gut functions, and food intake, as well as playing important signaling roles in the brain. Brain-derived CCK regulates circuits regulating reward, anxiety, aggression, and sexual behavior. In invertebrates, CCK-like peptides (sulfakinins, SKs) are, with a few exceptions, produced by brain neurons only. Invertebrate SKs regulate food ingestion by a variety of mechanisms. Also, regulation of digestive enzymes has been reported. The genetically tractable fly Drosophila melanogaster has been extensively investigated with respect to neuropeptide signaling at the cellular level. These studies have also advanced our understanding of SK signaling mechanisms in regulation of feeding, but also in gustatory sensitivity, locomotor activity, aggression, and reproductive behavior. In Drosophila, a set of only eight SK-expressing brain neurons plays critical roles in regulation of these competing behaviors. In male flies, they integrate internal state and external stimuli to diminish sex drive and increase aggression. The same neurons also diminish sugar gustation and reduce food intake. Although several functional roles of CCK/SK signaling are conserved between Drosophila and mammals, available data suggest that the underlying neuronal systems and mechanisms differ.