There has been increased interest in the use of naturally occurring compounds with chemopreventive and chemotherapeutic effects in the treatment of cancers. This review summarizes the most recent advances that provide new insights into the molecular mechanisms underlying the apoptotic potential of nutritional supplements and herbs. Apoptosis is an essential process in the pathogenesis of cancer and its mechanisms can be subdivided into either a death receptor-dependent extrinsic pathway or an independent (mitochondrial or intrinsic) pathway. Nutritional supplements and herbs can exert their effects on such pathways separately, sequentially, or in a manner of "crosstalk" between pathways. A strong correlation between the early collapse of the mitochondrial membrane potential and apoptosis was found for most nutritional supplements and herbs that have been studied. These observations provide examples of the development of mitochondrial targeting strategies for cancer therapy.