Mechanical stress is essential for the survival of cells and the maintenance of tissues. However, the mechanisms of cell response to mechanical stress are not fully elucidated due to the diversity of mechanical stresses and mechanosensors. Ion channels, cytoskeletons, or adherence molecules are supposed to be most probable candidates for the mechanosensor in cells. In addition, a release of extracellular messengers including ATP in response to mechanical stresses is thought to be an important mechanism of the mechanosensing in the tissue. Here, we review how these mechanosensing machineries detect various mechanical stresses and work in cells.