After formation of the giga-seal, the membrane patch can be stimulated by hydrostatic or osmotic pressure gradients applied across the patch. This feature led to the discovery of stretch-sensitive or mechanosensitive (MS) channels, which are now known to be ubiquitously expressed in cells representative of all the living kingdoms. In addition to mechanosensation, MS channels have been implicated in many basic cell functions, including regulation of cell volume, shape, and motility. The successful cloning, overexpression, and crystallization of bacterial MS channel proteins combined with patch clamp and modeling studies have provided atomic insight into the working of these nanomachines. In particular, studies of MS channels have revealed new understanding of how the lipid bilayer modulates membrane protein function. Three major membrane protein families, transient receptor potential, 2 pore domain K(+), and the epithelial Na(+) channels, have been shown to form MS channels in animal cells, and their polymodal activation embrace fields far beyond mechanosensitivity. The discovery of new drugs highly selective for MS channels ("mechanopharmaceutics") and the demonstration of MS channel involvement in several major human diseases ("mechanochannelopathies") provide added motivation for devising new techniques and approaches for studying MS channels.