Multiple myeloma is a uniformly fatal cancer killing about 12,000 individuals annually in the U.S. alone. We have recently discovered that two agents isolated from natural sources, chaetocin and cis-bixin, have impressive and selective anti-myeloma activity in freshly collected patient bone marrow cells, making them attractive agents for further development. We now propose further mechanistic studies and chemical modifications of these compounds in efforts to 1) determine how they kill myeloma cells, 2) optimize their effects, and 3) advance their development toward intended eventual human anti-myeloma clinical trials.