The development of coronary stent has revolutionized the field of interventional cardiology by reducing the incidence of restenosis after balloon angioplasty. Despite significant progress in its prevention and treatment, however, in-stent restenosis (ISR) is still common, and remains a challenge for the interventional cardiologist. Restenosis after stent implantation is mainly caused by neointimal proliferation through the stent struts. Currently, there are three major factors has been demonstrated to be contributors for ISR, namely patients-, lesion- and genetic-related factors in large number of clinical trials. However, the triggers and pathophysiological mechanisms for ISR are not fully elucidated. Experimental as well as clinical studies indicate a marked activation of inflammatory cells at the site of stent structs, which are likely to play a key role in the process of neointimal proliferation and stent restenosis. Those data suggest that inflammation may be a major contributor for ISR. In fact, coronary stenting is a strong inflammatory stimulus and the acute systemic response to local inflammation produced by coronary stenting is highly individual and predicts restenosis and event-free survival. Thus, the attention should be paid on anti-inflammatory therapeutic approaches for ISR, and the benefit of anti-inflammatory therapy during the periprocedural period and long-term follow-up is dependent on the inflammatory status. Measurement of cytokine and acute phase proteins, such as C-reactive protein, therefore, may be important to identify high-risk subjects and develop specific treatment tailored to the individual patients.