Betulinic acid (BA) is a naturally occurring pentacyclic triterpene that exhibits a variety of biological activities including potent antitumor properties. This anticancer activity has been linked to its ability to directly trigger mitochondrial membrane permeabilization, a central event in the apoptotic process that seals the cell's fate. In contrast to the potent cytotoxicity of BA against a variety of cancer types, nonmalignant cells and normal tissue remained relatively resistant to BA, indicating a therapeutic window. Since agents that exert a direct action on mitochondria may trigger cell death under circumstances in which standard chemotherapeutics fail, there is increasing interest to develop such compounds as experimental cancer therapeutics. Thus, mitochondrion-targeted agents such as BA hold great promise as a novel approach to bypass certain forms of drug resistance in human cancers.