Early stages of vascular development include endothelial cell differentiation in a network of arteries, veins, and lymphatics. Subsequently, to respond to the specific needs of the organs, endothelial cells acquire specialized properties such as permeability control, expression of specific transcellular transport systems, membrane adhesive molecules, and others. Endothelial cell differentiation depends on communication between the surrounding tissues, which is mediated by growth and differentiation factors able to activate specific gene expression programs. Recent reports underline the important role of the Wnt system in vascular morphogenesis in the embryo and in organ-specific endothelial differentiation. Wnt signaling regulates fundamental aspects of development, including cell fate specification, proliferation, and survival, and may use different receptors and signaling pathways. Both loss- and gain-of-function experiments of members of the Wnt signaling pathway were found to cause marked alterations of vascular development and endothelial cell specification. Furthermore, altered Wnt signaling in the endothelium may contribute to pathological conditions such as retinopathies, pulmonary arterial hypertension, stroke, and others. Continued progress in this field holds the potential to identify novel therapeutics for the treatment of these diseases.