Since the late 1990s, there has been a steady decline in cancer-related mortality, in part related to the introduction of so-called targeted therapies. Intended to interfere with a specific molecular pathway, these therapies have, paradoxically, led to a number of effects off their intended cancer tissue or molecular targets. The latest examples are tyrosine kinase inhibitors targeting the Philadelphia Chromosome mutation product, which have been associated with progressive atherosclerosis and acute vascular events. In addition, agents designed to interfere with the vascular growth factor signaling pathway have vascular side effects ranging from hypertension to arterial events and cardiomyocyte toxicity. Interestingly, the risk of cardiotoxicity with drugs such as trastuzumab is predicted by preexisting cardiovascular risk factors and disease, posing the question of a vascular component to the pathophysiology. The effect on the coronary circulation has been the leading explanation for the cardiotoxicity of 5-fluorouracil and may be the underlying the mechanism of presentation of apical ballooning syndrome with various chemotherapeutic agents. Classical chemotherapeutic agents such as cisplatin, often used in combination with bleomycin and vinca alkaloids, can lead to vascular events including acute coronary thrombosis and may be associated with an increased long-term cardiovascular risk. This review is intended to provide an update on the evolving spectrum of vascular toxicities with cancer therapeutics, particularly as they pertain to clinical practice, and to the conceptualization of cardiovascular diseases, as well. Vascular toxicity with cancer therapy: the old and the new, an evolving avenue.