Immunosuppressive drugs (ISDs) have a major impact on the development and progression of cardiac allograft vasculopathy (CAV), the main cause of cardiac allograft loss and a leading cause of death beyond the 1st post-transplant year. The influence of ISDs on the development and progression of CAV is complex. In spite of their high potency to suppress the alloimmune response (prevention of allograft rejection) which plays an essential role in the pathogenesis of CAV, the immunosuppressive regimens which were used in the past were not able to entirely prevent the development of CAV. This can be explained by the fact that several non-alloimmune insults such as brain death, organ preservation, surgical trauma, ischemia-reperfusion, diabetes, hypertension, hyperlipidemia, cytomegalovirus infection etc. are also involved in the development or progression of CAV. Some of these insults are not affected by immunosuppression, whereas others can be even aggravated by certain ISDs, particularly by calcineurin inhibitors (CNIs), but also by glucocorticosteroids and proliferation signal inhibitors (PSIs). Certain ISDs, especially CNIs, also have direct toxic effects on vascular endothelial and smooth muscle cells inducing endothelial dysfunction and proliferation of both smooth muscle cells and fibroblasts which promotes the development and progression of CAV. Other ISDs like PSIs and mycophenolate mofetil appeared able to delay the onset of CAV and reduce its progression, especially by their inhibitory effects on smooth muscle cell migration and proliferation. The present article reviews the data available on the impact of different ISDs and regimens on the development and progression of CAV.