Mitochondria play pivotal roles in most eukaryotic cells, ranging from energy production to regulation of apoptosis. As sites of cellular respiration, mitochondria experience accumulation of reactive oxygen species (ROS) due to damage in electron transport chain carriers. Mutations in mitochondrial DNA (mtDNA) as well as nuclear DNA are reported in various cancers. Mitochondria have a dual role in cancer: the development of tumors due to mutations in mitochondrial genome and the generation of ROS. Impairment in the mitochondria-regulated apoptosis pathway accelerates tumorigenesis. Numerous strategies targeting mitochondria have been developed to induce the mitochondrial (i.e. intrinsic) apoptosis pathway in cancer cells. This review elaborates the roles of mitochondria in cancer with respect to mutations and apoptosis and discusses mitochondria-targeting strategies as cancer therapies to enhance the killing of cancer cells.