Macromolecules comprise a growing group of new drugs with great clinical promise. To date, the therapeutic application of these drugs has been limited, because they are effective only when administered parenterally. Unfortunately, macromolecular drugs are not absorbed following nonparenteral dosing, because the mechanisms of the human body are designed to degrade and/or 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. We review our own novel work in this area in some detail, including the methods developed for the synthesis of the delivery agents, in vitro screening techniques developed to select compounds for in vivo testing, and the results of in vivo screening in both rats and primates, including preliminary safety and efficacy studies. Finally, the results of Phase I clinical studies showing the oral delivery of heparin are presented.