The endothelium is a highly dynamic cell layer that is involved in a multitude of physiologic functions, including the control of vasomotor tone, the trafficking of cells and nutrients, the maintenance of blood fluidity, and the growth of new blood vessels. Over the past several decades, advances in basic research of the endothelium have far outstripped those in the clinic. One explanation for this growing bench-to-bedside chasm relates to the inflexible and largely outdated nature of the present-day medical infrastructure. The constraints of medical subspecialization have created a conceptual blind spot, namely, the inability to appreciate the endothelium for what it is: a cell layer that is teeming with life, every bit as active as any other organ in the body. The overall goal of this review is to bring the endothelium “to life” and to argue that future breakthroughs in biomedicine are contingent on acceptance of the endothelium as a bona fide organ system.