Endothelial cells can toggle back and forth between differentiated and relatively undifferentiated states with comparative ease. This is an important characteristic, particularly in adult tissues where the constitutive endothelial cell phenotype is quiescent. It enables rapid repair of wounds, renewal of the vascular intima in parts of the circulatory system with high flow and turbulence, and is essential to the cyclic function of reproductive organs. However, the ability to dedifferentiate can be a severe disadvantage when it is subverted to the support of disease processes such as tumor growth and metastasis. The control of endothelial cell differentiation state is, therefore, a matter of significance to investigators of basic developmental mechanism, as well as those studying an array of neovascular disorders. Recently, studies have advanced beyond the identification of extracellular triggers and overt cellular responses to the analysis of signal transduction pathways and nuclear events. This review focuses on the nuclear protein pigpen that is found in the right place at the right time, and with the necessary equipment, to modulate endothelial cell differentiation. We project that when we better understand the relationship of pigpen to its upstream regulators and downstream effectors, we will also have a better understanding of the mechanisms underlying capillary morphogenesis.