All mammalian tissues examined to date have two forms of guanylate cyclase with apparently different properties. From the studies in several laboratories, we suggest the following mechanisms for the possible regulation of guanylate cyclase activity: (1) factors that could alter the apparent cooperative nature of the enzyme, (2) interactions of metal ions with the substrate or enzyme, (3) factors that could overcome inhibition by ATP, (4) mechanisms that could regulate the interconversion of latent and active forms of the enzyme, (5) possible translocation of particulate and soluble forms of the enzyme, and (6) induction or repression of the enzyme.