The tissues of the body are continually subjected to mechanical stimulation by external forces, such as gravity, and internally generated forces, such as the pumping of blood or muscle contraction. Within a physiological range, the forces elicit adaptive responses acutely (to rapidly alter function) and chronically (to remodel tissue structure to optimize load-bearing capabilities). When the forces exceed certain thresholds, injury results. To understand the mechanisms of mechanical injury at the cellular level, we must analyze the structural response of the cell to various modes of deformation and examine the biological consequences of the structural alterations caused by the trauma. This chapter reviews the mechanics of cell membrane deformation and failure. Evidence for the strain-rate-dependent, transient disruption of cell membranes, or mechanoporation, is presented for a variety of cell types. The complex interactions between the structural damage and the biological sequelae are illustrated using clinically relevant forms of cell injury. Finally, novel therapeutic approaches targeting membrane integrity are described.