Molecular motors, such as myosin, kinesin, and dynein, convert the energy released by the hydrolysis of ATP into mechanical work, thus allowing them to undergo directional motion on cytoskeletal tracks. A pivotal step in the chemomechanical transduction in myosin motors occurs after they bind to the actin filament, which triggers the release of phosphate (P-i, product of ATP hydrolysis) and the rotation of the lever arm. Here, we investigate the mechanism of phosphate release in myosin VI using extensive molecular dynamics simulations involving multiple trajectories of several mu s. Because the escape of phosphate is expected to occur on time-scales on the order of milliseconds or more in myosin VI, we observed P-i release only if the trajectories were initiated with a rotated phosphate inside the nucleotide binding pocket. We discovered that although P-i populates the traditional "back door" route, phosphate exits through various other gateways, thus establishing the heterogeneity in the escape routes. Remarkably, we observed that the release of phosphate is preceded by a stepwise hydration of the ADP-bound magnesium ion. The release of the anion occurred only after four water molecules hydrated the cation (Mg2+). By performing comparative structural analyses, we show that hydration of magnesium is the key step in the phosphate release in a number of ATPases and GTPases. Nature may have evolved hydration of Mg2+ as a general molecular switch for P-i release, which is a universal step in the catalytic cycle of many machines that share little sequence or structural similarity.