Stretch-activated or mechanosensitive channels transduce mechanical forces into ion fluxes across the cell membrane. These channels have been implicated in several aspects of cardiovascular physiology including regulation of blood pressure, vasoreactivity, and cardiac arrhythmias, as well as the adverse remodeling associated with cardiac hypertrophy and heart failure. This review discusses mechanosensitive channels in skeletal muscle and the cardiovascular system and their role in disease pathogenesis. We describe the regulation of gating of mechanosensitive channels including direct mechanisms and indirect activation by signaling pathways, as well as the influence on activation of these channels by the underlying cytoskeleton and scaffolding proteins. We then focus on the role of transient receptor potential channels, several of which have been implicated as mechanosensitive channels, in the pathogenesis of adverse cardiac remodeling and as potential therapeutic targets in the treatment of heart failure.