Notch signaling is a major pathway in cell fate decisions. Since the first reports showing the major role of Notch in embryonic development, a considerable and still growing literature further highlights its key contributions in various pathological processes during adult life. In particular, Notch is now considered as a major player in vascular homeostasis through the control of key cellular functions. In parallel, confounding evidence emerged that inflammatory responses regulate Notch signaling in vitro in endothelial cells, smooth muscle cells or vascular infiltrating cells and in vivo in vascular and inflammatory disorders and in cardiovascular diseases. This review presents how inflammation influences Notch in vascular cells and, reciprocally, emphasizes the functional role of Notch on inflammatory processes, notably by regulating key cell functions (differentiation, proliferation, apoptosis/survival, activation). Understanding how the disparity of Notch receptors and ligands impacts on vasculature biology remains critical for the design of relevant and adequate therapeutic strategies targeting Notch in this major pathological context.