The Notch signalling pathway is a highly conserved cell–cell signalling mechanism that plays a central role in the development and maturation of most vertebrate organs. In vertebrates, Notch receptors, several ligands, and components of the downstream signalling machinery are expressed in the vessel. Over the past decade, numerous studies have highlighted the critical role of the Notch pathway in the vasculature. The goal of this review is to summarize our current understanding of the contribution of Notch signalling in smooth muscle cells to vascular development and physiology. We further discuss the growing clinical importance of this pathway in human pathological conditions involving the vasculature, namely cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Alagille syndrome, and pulmonary arterial hypertension.