Transforming growth factor (TGF)-beta is a multifunctional protein that initiates its diverse cellular responses by binding to and activating specific type I and type II serine/threonine kinase receptors. TGF-beta can act as a regulator of proliferation, migration, survival, differentiation, and extracellular matrix synthesis in endothelial cells and vascular smooth muscle cells, as well as in the maintenance of vascular homeostasis. Importantly, genetic studies in humans have revealed the pivotal role of TGF-beta as well as its signaling components in angiogenesis. Mutations in two TGF-beta receptors (ie, the activin receptor-like kinase (ALK) 1 and the accessory TGF-beta receptor endoglin) have been linked to vascular disorders named hereditary hemorrhagic telangiectasia. In addition, knockout mice for the different components of the TGF-beta signaling pathway have shown that TGF-beta is indispensable for angiogenesis. Recent studies have revealed that TGF-beta can regulate vascular homeostasis by balancing the signaling between two distinct TGF-beta type I receptors (ie, the endothelial-restricted ALK1 and the broadly expressed ALK5 receptors). The activation of these receptors has been shown to induce opposite effects on endothelial cell behavior and angiogenesis. In this review, we will present recent advances in understanding the role of TGF-beta signaling in endothelial cells as well as the underlying molecular mechanisms by which perturbation of this pathway can lead to vascular disorders.