Connexins form gap junction channels that provide a hydrophilic path between cell interiors. Some connexins, particularly the lens connexins, Cx46 and Cx50 and their orthologs, can form functional hemichannels in nonjunctional membranes. These hemichannels are a nonselective conduit to the extracellular medium and may jeopardize cell survival. The physiological function of hemichannels has remained elusive, but it has been postulated that hemichannels are involved in ATP-release caused by mechanical stimulation. Here we show with single-channel and whole cell electrophysiological studies that Cx46 hemichannels are mechanosensitive, like other families of ion channels and membrane-bound enzymes. The hemichannel response to mechanical stress is bipolar. At negative potentials stress opens the channel, and at positive potentials stress closes it. Physiologically, Cx46 hemichannels may assist accommodation of the ocular lens by providing a transient path for volume flow as the lens changes shape.