Coronary restenosis has proven to be the "Achilles heel" of percutaneous coronary interventions, frequently leading to repeated procedures. The pathogenesis of restenosis can be divided into four phases: early elasic recoil (hours to days), mural thrombus formation (hours to days), neointimal proliferation and extracellular matrix formation (weeks), and chronic geometric arterial changes (months). Restenosis is device nonspecific except for intravascular stents, which can eliminate elastic recoil and prevent geometric vessel changes, leading to decreased restenosis. Of all antithrombotics tried so far, only an inhibitor of the platelet IIb/IIIa integrin, which may lead to early vessel wall passivation, has shown reduction of clinical restenosis. Trapidil (antiproliferative agent) and angiopeptin (somatostatin analog) have also resulted in improved restenosis rates. The field of local drug delivery is currently under investigation in association with radiation or molecular therapy. The current specific target of these approaches is the neointimal proliferation, especially because this is the most dominant mechanism of restenosis after stent placement. Evaluation of these novel methods is complex and interrelates the delivery system with the therapeutic agent administered. However, they provide the means for very specific and timely interruption of the pathogenic process that may lead to better understanding and, ultimately, elimination of restenosis.