During the last few decades, with the evolution of techniques and materials and the increasing experience of operators, percutaneous coronary interventions (PCI) have become an equally efficient alternative to coronary artery bypass grafts for the treatment of most coronary stenoses. Bare-metal stent implantation represented a major step forward, compared with plain old balloon angioplasty (POBA), by improving the immediate angiographic success. However, the incidence of in-stent restenosis (ISR) remained unacceptably high. Development of the drug-eluting stent (DES) significantly improved the outcome of PCI by dramatically abating the rate of ISR and reducing the incidence of target lesion revascularization. However, ISR has not been eliminated and the persistence of metal vessel scaffolding also raises concern regarding the occurrence of late or very late stent thrombosis. POBA and stent implantation have been shown to induce a local and systemic inflammatory response, whose magnitude is associated with worse clinical outcome, and they increase the risk of ISR. C-reactive protein, a marker of systemic inflammation, has been demonstrated to predict clinical and angiographic outcome after POBA or bare-metal stent implantation. However, conflicting data regarding the prognostic value of C-reactive protein following DES implantation are available. In this paper, we review the literature regarding the clinical and pathophysiological association between inflammation and prognosis after DES implantation and suggest some possible therapeutic approaches to reduce inflammatory burden with the aim to improve clinical and angiographic outcome after PCI.