Each component of a drug-eluting stent (DES) contributes to the safety of the device. Continuous efforts are being dedicated to the search of the optimal compromise between facility of use, safety and long-term efficacy. Shorter balloons reduce the vascular trauma beyond the stent struts; the metallic composition of the stent platform and the platform itself interact with the vascular wall in a long-lasting equilibrium between radial force, vessel patency and reparative cellular regrowth. The modality of drug elution is largely regulated by the chosen drug carrier, rather than by the chemical properties of the drug itself. Drug elution can be accomplished by permanent polymers that remain in the vessel wall forever, by biodegradable polymers that leave the naked metallic structure behind after their complete absorption, or even by direct release of the drug from stent reservoirs. The clinical performance of DESs has been exhaustively assessed in a large number of studies that have showed rapid and continuous improvements, from the first-generation DESs to the latest devices, based on substantial changes in stent design and polymer composition.