Blood vessels perfuse all tissues in the body and mediate vital metabolic exchange between tissues and blood. Increasing evidence, however, points to a direct role for paracrine signaling between blood vessel cells and surrounding target organ cells, during embryonic development and cell differentiation. Understanding the nature of this signaling and its heterogeneity, both in the embryo and in adult tissues, may not only provide insights into mechanisms for normal developmental cell fate decisions, but could also lead to novel targeted therapeutic approaches for a variety of diseases such as heart disease, diabetes or cancer.