The unique position of endothelial cells (ECs), between the intravascular and extravascular spaces, has given them a wide variety of functions—the ability to sense, monitor and transfer molecules from plasma to surrounding tissues, and vice versa. Loss of these physiological functions is a critical step in the etiology of various clinical syndromes, such as atherosclerosis, thrombosis and disruption of the Blood Brain Barrier. In spite of being continuously exposed to circulating lipids and, in some cases to lipids that have accumulated in sub-endothelial regions, ECs were long thought to function as an inert barrier through which lipid exchange between the plasma and surrounding tissues occurs. An accumulating body of evidence however, indicates that lipids act directly on ECs, and activate intracellular signaling cascades [1]. This review will examine the receptors as well as signaling pathways activated in ECs by different lipid classes. It is useful to discuss these topics in terms of in vitro vs. in vivo findings, with particular emphasis on recent work, taking advantage of small animal models used to study lipid signaling in the endothelium.