Coronary heart disease is one of the most important causes of death in human, and consumes vast medical resources. Percutaneous coronary intervention (PCI) has been a significant breakthrough for its treatment. However, clinical application has been hampered by in-stent restenosis (ISR). Although drug eluting stent (DES) has reduced the occurrence of restenosis, incidence of ISR is still about 5% to 10%. The main reasons for restenosis after PCI are hyperplasia of vascular endothelial cells and smooth muscle cell migration. The exact mechanism of personalized differences in restenosis is not clear yet, but there may be a variety of risk factors. In addition to aging, smoking and diabetes, an increasing number of studies have found that genetic and epigenetic factors play an important role in ISR. In this article, authors have reviewed genetic and epigenetic factors on the progression of ISR, which may help to determine the genetic risk factors in patients with ISR after PCI.