Endothelial cells translate hemodynamic forces into biochemical signals that regulate vascular homeostasis through a process called mechanotransduction. Over the past decades, the study of this physiological process has received significant attention, leading to the identification of molecular structures that detect changes in shear stress. However, the functional capacity of these mechanosensors is compromised under conditions such as obesity, diabetes, and aging, resulting in impaired mechanotransduction. Such impaired mechanotransduction leads to endothelial dysfunction, a key early component of cardiovascular disease. This highlights the importance of studying the molecular and cellular mechanisms underlying endothelial mechanotransduction and its dysfunction. In this chapter, putative molecular components of endothelial mechanotransduction, their signaling pathways, and alterations under both physiological and pathological conditions will be discussed. Accurate identification of these components and a deep understanding of the mechanotransduction mechanisms in which they participate are needed to develop novel therapeutics for cardiovascular disease.