GPCRs are present on every regulatable cell in the body. While most approved drugs act on these receptors, such drugs target only a small fraction of GPCRs, with most representing full agonists and/or classical antagonists. Recent recognition of advantages of biased agonists and allosteric modulators has created new opportunities for drug development. The type 1 cholecystokinin receptor (CCK1R) is a potential target for obesity drugs, based on action at vagal afferent neurons to induce satiety. A non-caloric satiety agent such as a CCK1R agonist would have the theoretical advantage of reducing meal size and frequency. Definition of site of action of CCK peptides was achieved using photoaffinity labeling and fluorescence. This orthosteric site was localized to the external surface of the bilayer, with contributions by receptor tail and loop regions. Full agonists of CCK1R, however, offer potential challenges for drug development, with high potency compounds often associated with side effects of nausea, abdominal cramping, and diarrhea, and theoretical concern related to potential trophic effects on the pancreas. Small molecule agonists have also been developed, and their site of action has been defined as a pocket high in the helical bundle region. This allosteric pocket has been demonstrated to be spatially distinct from that of the site of action of CCK. Distinct conformations of this pocket have been defined for CCK1R vs. its closest relative, CCK2R, and for active and inactive states. A strategy to circumvent problems associated with full agonist drugs is a positive allosteric modulator devoid in intrinsic activity. Such an agent would have the advantage of only being active for a finite period of time after meal ingestion. One strategy to develop such a drug would be modification of the agonist trigger of an allosteric agonist. Another target for allosteric regulation is the lipid face of the helical bundle. Here, too, receptor mutagenesis was utilized to explore the site of action of cholesterol and other related molecules for lateral allosteric modulation of this receptor. Utilizing the insights of the molecular basis of binding and action of orthosteric peptide agonists of GPCRs, as well as sites of allosteric ligand action, provides exciting new directions for drug development and regulation of signaling at these receptors.