Transplant vasculopathy (TV) remains the most common cause of long-term mortality in cardiac transplant recipients. Treatment options are limited, and traditionally, the only definitive treatment was retransplantation. An increasing understanding of the pathophysiology of TV in recent years, in particular as an immune phenomenon, has stimulated important research into new strategies for the prevention of the progression of this condition. Coupled with this, the emerging evidence in recent years of the role of resident and circulating progenitor cells in the pathogenesis of vascular disease has opened new horizons in the understanding of the pathogenesis of TV and, in addition, of the potential mechanisms underlying the beneficial effects of new and exciting therapeutic strategies. In this paper, the current understanding of the pathogenesis of TV and the possible role of stem and progenitor cells in this regard will be described. Recent data on new pharmacotherapeutic options for the prevention and treatment of TV will be examined, and the possible mechanistic contribution of circulating and resident stem and progenitor cells will be discussed. Finally, the implications of the current status of our understanding for the development of new innovative therapeutic options for TV will be explored.