Percutaneous angioplasty is a nonsurgical method able to restore patency in atherosclerotic blood vessels through the expansion of a balloon. The clinical outcome of this technique has been significantly enhanced by the combined deployment of a stent. Although stents are successful in the majority of cases, a large percentage of patients (20–30%) still suffer a second vessel lumen reduction known as in-stent restenosis. In-stent restenosis is recognized to be caused by the mechanical and foreign body challenges elicited by the device. Drug-eluting stents have been recently made available to tackle restenosis, but their short clinical history and high costs may limit their future use. The present review links the most recent biologic findings related to in-stent restenosis to the devices’ phyisico-chemical features in an attempt to demonstrate that a new generation of stents may be developed without the need of drug elution.