Cells sense their physical environment through mechanotransduction-that is, by translating mechanical forces and deformations into biochemical signals such as changes in intracellular calcium concentration or activation of diverse signalling pathways. In turn, these signals can adjust cellular and extracellular structure. This mechanosensitive feedback modulates cellular functions as diverse as migration, proliferation, differentiation, and apoptosis and is critical for organ development and homeostasis. Consequently, defects in mechanotransduction-often caused by mutations or misregulation of proteins that disturb cellular or extracellular mechanics-are implicated in the development of a wide array of diseases, ranging from muscular dystrophies and cardiomyopathies to cancer progression and metastasis.Mechanotransduction describes the cellular processes that translate mechanical stimuli into biochemical signals, thus allowing cells to adapt to their physical environment. Extensive research over the last decades has identified several molecular players involved in cellular mechanotransduction (Box 1); however, many components, and especially the identity of the primary mechanosensor(s), remain incompletely defined.Research in mechanotransduction has often focused on sensory cells, such as hair cells in the inner ear. These specialized cells often have evolved specific cellular structures ( Fig. 1) that are tailored to transduce mechanical inputs into biochemical signals (for example, by opening ion channels in response to applied forces) and thus provide a good model to study cellular mechanosensing. Subsequently, it has become apparent that mechanotransduction signalling has a critical role in the maintenance of many mechanically stressed tissues such as muscle, bone, cartilage, and blood vessels; consequentially, research has expanded to diverse celltypes such as myocytes, endothelial cells, and vascular smooth muscle cells. Mechanotransduction is now emerging to be involved in a much broader range of cellular functions, not just in a subset of specialized cells and tissues. For example, stem-cell differentiation can be steered towards specific fates based on the geometry and stiffness of the substrate on which the cells are grown on 1 , and intercellular physical interactions such as tension and adhesion might be as important in embryonic development as concentration gradients of morphogenic factors (see the Review by Wozniak and Chen in this issue.)In this Review, we discuss how mutations and modifications that interfere with normal mechanotransduction and cellular sensitivity to mechanical stress could be implicated in a wide spectrum of diseases that range from loss of hearing to muscular dystrophies and cancer (Table 1). Many of these diseases share few similarities at first sight. How could muscular dystrophies be related to atherosclerosis or kidney failure? In the following, we will highlight some of these disorders and discuss how they could be traced back, at least in part, to defects in mec...