Animal cells have only three sources of free energy: chemical, electrical and mechanical potential. We know almost nothing about the latter. The cytoskeleton and the cell membrane are inhomogeneous, anisotropic and viscoelastic and plastic making mechanical stimulus definition a problem. We have probed both mechanical channels and physiological stresses in the structural cytoskeleton and learned much of our ignorance of cell mechanics. This is a problem for translational medicine since nearly all diseases involve changes in cell shape that are driven by forces and they are coupled to electrical and chemical potentials. We discovered mechanosensitive ion channels (MSCs), but only recently have the eukaryotic cationic channels been cloned. The family is named Piezo and consists of has Piezo 1 & 2 and are specifically inhibited by the peptide GsMTx4. The channels seem to serve as cellular nociceptors informing the cytoskeleton to enforce of regions of the bilayer that are under pathologic stress. Thus, in a healthy body HSCs are closed and unaffected by GsMTx4. The human Piezo gene was cloned from HEK cells and the mutants that cause hereditary anemia exhibited slow inactivation leading to excessive cation flux in red cells. Lipid bilayer stress that affects the channels is a function of stress in the cortical cytoskeleton, so all structural members of the cortex affect channel activity. We have created a family of genetically coded fluorescent probes to measure stress in those components such as actin, actinin, spectrin, etc., as well as the extracellular matrix including collagen.