Signal transduction by vascular endothelial growth factors (VEGFs) through their cognate VEGF receptor tyrosine kinases follows the consensus scheme for receptor tyrosine kinases. Thus, binding of ligand induces receptor dimerization and activation of the tyrosine kinase through transphosphorylation between receptor molecules, leading to initiation of intracellular signal transduction pathways. Certain signal transduction pathways are shared with most, if not all, receptor tyrosine kinases, whereas some may be unique (e.g., transduced only by VEGF receptors). Indications that such unique signaling pathways may be discerned only when VEGF receptors are expressed in their proper context (i.e., in endothelial cells of microcapillary origin). In this chapter, we describe a number of methods for the study of signal transduction in endothelial cells. We describe how to isolate and examine endothelial cell lines. We also describe the embryoid body model representing vasculogenesis and angiogenesis, the procedure for subcutaneous Matrigel plugs, and, finally, how to construct gene-targeted mouse models. We emphasize the need for validation of in vitro data in more complex models, where endothelial cells reside in their proper three-dimensional context.