Members of the transforming growth factor-β (TGF-β) family play pivotal roles in development and disease. These cytokines elicit their pleiotropic effects on cells, including endothelial and mural cells, through specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. This review highlights recent progress in our understanding of TGF-β signaling in vascular development and angiogenesis and of how perturbed TGF-β signaling might contribute to vascular pathologies, tumor angiogenesis and tumor progression. Recent research has provided exciting insights into the role of the TGF-β type I receptor (ALK1) in tumor angiogenesis and the curative effects of thalidomide on vascular malformations in hereditary hemorrhagic telangiectasia (HHT). These advances provide opportunities for the development of new therapies for diseases with vascular abnormalities.