Restenosis following stent implantation diminishes the procedure's efficacy influencing long-term clinical outcomes. Stent-based drug delivery emerged a decade ago as an effective means of reducing neointimal hyperplasia by providing localized pharmacotherapy during the acute phase of the stent-induced injury and the ensuing pathobiological mechanisms. However, drug-eluting stent (DES) restenosis may still occur especially when stents are used in complex anatomical and clinical scenarios. A DES consists of an intravascular metallic frame and carriers which allow controlled release of active pharmaceutical agents; all these components are critical in determining drug distribution locally and thus anti-restenotic efficacy. Furthermore, dynamic flow phenomena characterizing the vascular environment, and shear stress distribution, are greatly influenced by stent implantation and play a significant role in drug deposition and bioavailability within local vascular tissue. In this review, we discuss the performance of DES and the interaction of the different DES components with the hemodynamic milieu emphasizing on the inhibition of clinical restenosis.