Podophyllotoxin is a plant-derived compound found in Podophyllum sp. that is used to produce semi-synthetic anticancer pharmaceuticals such as etoposide, teniposide, and etoposide phosphate. This chapter describes the role of biotechnology to produce podophyllotoxin and our attempts to domesticate Podophyllum peltatum L., also known as the American mayapple. The domestication research on mayapple included surveys of the natural population, identification of high yielding genotypes, propagation, cultivation, sustainable harvest procedures and the development of protocols for in vitro germplasm bank.