Myosin is an ATP-hydrolyzing motor that is critical in muscle contraction. It is well established that in the hydrolysis that it catalyzes a water molecule attacks the gamma-phosphate of an ATP bound to its active site, but the details of these events have remained obscure. This is mainly because crystallographic search has not located an obvious catalytic base near the vulnerable phosphate. Here we suggest a means whereby this dilemma is probably overcome. It has been shown [Fisher, A. J., et al. (1995) Biochemistry 34, 8960-8972; Smith, C. A., and Rayment, I. (1996) Biochemistry 35, 5404-5417] that in an early event, Arg-247 and Glu-470 come together into a "salt-bridge". We suggest that in doing so they also position and orient two contiguous water molecules; one of these becomes the lytic water, perfectly poised to attack the bound gamma-phosphorus. Its hydroxyl moiety attacks the phosphorus, and the resulting proton transfers to the second water, converting it into a hydronium ion (as is experimentally observed). It is shown in this article how these central events of the catalysis are consistent with the behavior of several residues of the neighboring region.