The motilin receptor (MTLR) represents a clinically useful pharmacological target, as agonists binding to the MTLR have gastroprokinetic properties. Motilin is a 22 amino acid peptide that potently stimulates gastrointestinal contractility. The biological effects of motilin are mediated by a Gq-coupled seven transmembrane protein, currently termed motilin receptor (MR) that shares significant sequence similarity with the ghrelin receptor. The motilin receptor is also activated by the antibiotic erythromycin; this interaction appears to mediate some of the gastrointestinal side effects of erythromycin. Although motilides (non-antibiotic derivatives of erythromycin) such as ABT-229 have been investigated for treatment of diabetic gastroporesis, the effectiveness has been limited by tachyphylaxis (decreased response to ligand) resulting from receptor downregulation. Agonists of the motilin receptor with reduced densensitization activity remain a potential treatment for disorders of gastric motility.