Restenosis is a complex disease for which the pathophysiological mechanisms have not yet been fully elucidated, but are thought to include inflammation, proliferation, and matrix remodeling. Over the years, many predictive clinical, biological, (epi)genetic, lesion-related, and procedural risk factors for restenosis have been identified. These factors are not only useful in risk stratification of patients, they also contribute to our understanding of this condition. Furthermore, these factors provide evidence on which to base treatment tailored to the individual and aid in the development of novel therapeutic modalities. In this Review, we will evaluate the available evidence on the pathophysiological mechanisms of restenosis and provide an overview of the various risk factors, together with the possible clinical application of this knowledge.