Macromolecules comprise a growing group of new therapeutics with great clinical promise. To date, these drugs are limited in their application because they are effective only when administered parenterally. Unfortunately, however, macromolecular drugs are not absorbed following nonparenteral dosing because the human body is designed to exclude them. To overcome the numerous obstacles to the noninvasive delivery of these drugs, various approaches are under investigation including the use of delivery agents to promote drug absorption. This review provides a summary of the novel approaches currently in progress in the areas of transdermal, transmucosal and oral delivery of macromolecular drugs facilitated by delivery agents.