The macrolide antibiotic erythromycin has been known to be associated with increased gastrointestinal motility since its introduction more than 35 years ago. Investigators have, thus, sought to take advantage of this side effect in patients with gastric stasis secondary to long-standing insulin-dependent diabetes mellitus (IDDM). The hormone motilin induces phase 3 contractions of the migrating motor complex (MMC) to induce peristalsis and facilitate gastric emptying in normal subjects. Patients with diabetic gastroparesis lack adequate phase 3 activity to effectively empty gastric contents. Exogenous motilin administered to animals and patients with diabetic gastroparesis has proven useful for promoting gastric emptying. However, motilin is expensive to produce and must be given intravenously. Erythromycin has been shown to induce premature phase 3 activity via stimulation of motilin receptors, so investigators evaluated its efficacy for the treatment of diabetic gastroparesis. Early studies in animals with experimental gastroparesis indicated that erythromycin may be a useful prokinetic agent. Human studies of both intravenous erythromycin and chronic oral erythromycin in patients with diabetic gastroparesis resistant to other prokinetic agents showed that gastric retention was indeed reduced and symptomatic improvement achieved. Even though erythromycin lost some of its prokinetic activity with chronic oral dosing, gastric retention was still significantly reduced compared to placebo or baseline. Although prokinetic agents like metoclopramide, domperidone and cisapride are effective for the treatment of patients with diabetic gastroparesis, tachyphylaxis and adverse effects are obstacles to their use. Erythromycin appears to be both effective and well tolerated in clinical studies. At this time it should be reserved for the treatment of patients with diabetic gastroparesis who are resistant to or intolerant of other prokinetic agents. Future research on erythromycin's long-term safety and comparative efficacy will further define its role.