Long-term in vivo administration of MSH induced melanogenesis in adult Rana pipiens. The melanin content of the skin was elevated to 2.6 times that of the control animals at the end of 8 weeks of administration. The elevation of the melanin content was accompanied by a parallel decrease of tyrosinase activity in the skin. Amphibian tyrosinase was found to be a soluble inactive enzyme which could be readily extracted by aqueous buffers and activated in vitro by trypsin. It was evenly distributed in pigmented and nonpigmented skin. These findings indicated that MSH-induced melanogenesis might be mediated through the release of an intracellular tyrosinase activator which was a trypsin-like proteolytic enzyme. Melanin synthesis catalyzed by the activated tyrosinase converted the partially melanized melanosomes to fully melanized melanin granules. In the process of melanization, the tyrosinase molecule was buried by increasing layers of deposited melanin and eventually became inaccessible to extraction by aqueous buffers. (Endocrinology88: 155, 1971)