Living organisms sense their physical environment through cellular mechanotransduction, which converts mechanical forces into electrical and biochemical signals. In turn, signal transduction serves a wide variety of functions, from basic cellular processes as diverse as proliferation, differentiation, migration, and apoptosis up to some of the most sophisticated senses, including touch and hearing. Accordingly, defects in mechanosensing potentially lead to diverse diseases and disorders such as hearing loss, cardiomyopathies, muscular dystrophies, chronic pain, and cancer. Here, we review the status of mechanically activated ion channel discovery and discuss current challenges to define their properties and physiological functions.