Restenosis after angioplasty or stenting remains the major limitation of both procedures. A vast array of drug therapies has been used to prevent restenosis, but they have proven to be predominantly unsuccessful. Recent trends in drug therapy have attempted to refine the molecular and biological targets of therapy, based on the assumption that a single biological process or molecule is critical to restenosis. In contrast, both stenting and brachytherapy, which are highly nonspecific, can successfully reduce restenosis after angioplasty or stenting, respectively. This review examines the biology of both angioplasty and stent stenosis, focussing on human studies. We also review the landmark human trials that have definitively proven successful therapies, such as stenting and brachytherapy. We suggest that the successful trials of stenting and brachytherapy and the failure of other treatments have highlighted the shortcomings of conventional animal models of arterial intervention, and gaps in our knowledge of human disease. In contrast to arguments advocating gene therapy, these studies suggest that the most likely successful drug therapy will have a wide therapeutic range, targeting as many of the components or biological processes contributing to restenosis as possible.