PURPOSE: Melanoma is the most invasive and deadly form of skin cancer. Few agents are available for treating advanced disease to enable long-term patient survival, which is driving the search for new compounds inhibiting deregulated pathways causing melanoma. Akt3 is an important target in melanomas because its activity is increased in approximately 70% of tumors, decreasing apoptosis in order to promote tumorigenesis. EXPERIMENTAL DESIGN: Because naturally occurring products can be effective anticancer agents, a library was screened to identify Akt3 pathway inhibitors. Isothiocyanates were identified as candidates, but low potency requiring high concentrations for therapeutic efficacy made them unsuitable. Therefore, more potent analogs called isoselenocyanates were created using the isothiocyanate backbone but increasing the alkyl chain length and replacing sulfur with selenium. Efficacy was measured on cultured cells and tumors by quantifying proliferation, apoptosis, toxicity, and Akt3 pathway inhibition. RESULTS: Isoselenocyanates significantly decreased Akt3 signaling in cultured melanoma cells and tumors. Compounds having 4 to 6 carbon alkyl side chains with selenium substituted for sulfur, called ISC-4 and ISC-6, respectively, decreased tumor development by approximately 60% compared with the corresponding isothiocyanates, which had no effect. No changes in animal body weight or in blood parameters indicative of liver-, kidney-, or cardiac-related toxicity were observed with isoselenocyanates. Mechanistically, isoselenocyanates ISC-4 and ISC-6 decreased melanoma tumorigenesis by causing an approximately 3-fold increase in apoptosis. CONCLUSIONS: Synthetic isoselenocyanates are therapeutically effective for inhibiting melanoma tumor development by targeting Akt3 signaling to increase apoptosis in melanoma cells with negligible associated systemic toxicity.