Mechanotransduction describes the molecular mechanisms by which cells response to changes in their physical environment by translating mechanical stimuli into biochemical signals. It is now clear that reactive oxygen species (ROS) and redox signaling play a crucial role in mechanotransduction analogous to their role in chemotransduction. This Forum has particular emphasis on ROS generation with altered mechanical stress, the upstream signal transduction pathways that initiate ROS production, and the downstream effectors that lead to physiological responses. There is particular emphasis on the role of ion channels in the initial response and the role of NADPH oxidases as the major source of ROS. The latter enzyme serves as the fulcrum of the mechanotransduction cascade. Although it seems likely that all cells are mechanosensitive to some degree, we have highlighted the responses of unicellular organisms (bacteria), bone cells, and particularly cells of the vasculature (endothelial cells and vascular smooth muscle cells). These cell types have been useful for studying the responses to altered osmotic pressure, hemodynamic pressure, shear stress, and compressive forces while exploring the link between signal transduction and physiological/pathophysiological responses.