The endothelial cells (ECs) of the primary vascular plexuses are among the first mesodermal derivatives to differentiate and become functional in the vertebrate embryo. Anatomically, ECs can be seen developing long before the heart initiates beating and, in gene expression studies, cells expressing endothelium-specific genes can be detected just after the end of gastrulation. In mammalian models, in embryo studies of the early events involved in the induction of ECs from their mesodermal precursors, a process termed vasculogenesis, are hampered by the technical difficulties inherent to the in utero development of the embryo. In addition, gene perturbations that result in impaired vasculogenesis are usually fatal and, as a consequence, the further remodeling and maturation of the vascular system, angiogenesis, cannot be investigated. Although embryonic stem cells and EC lines represent useful systems for the investigation of the signaling mechanisms involved during vasculogenesis and/or angiogenesis, due to their cell homogeneity and low anatomical complexity, these signaling mechanisms may well not be fully applicable to the embryo environment. Thus, model systems such as Xenopus and zebrafish, in which embryos develop externally and in a less circulation-dependent manner, offer an invaluable opportunity for the study of the early development of the vascular system. However, because the zebrafish is less amenable for transplantation and lineage-labeling experiments and, critically, because it lacks smooth muscle cells and a lymphatic system, Xenopus appears to be more suited for the study of some aspects of blood vessel development. Therefore, fate maps of the different blood vessels can be generated in Xenopus, and the importance of the interaction between ECs and smooth muscle cells during blood vessel formation can be studied.