Mitochondrion is a multifunctional organelle in a cell, and it is one of the important targets of antitumor therapy. Conventional mitochondrial targeting strategies can hardly distinguish the mitochondria in cancer cells from those in normal cells, which might raise a concern about the biosafety. Recent studies suggest that a relatively high temperature of mitochondria exists in cancer cells. We named it tumor intrinsic mitochondrial overheating (TIMO). By taking advantage of the difference in mitochondrial temperatures between cancer cells and normal cells, therapeutic agents can be specifically delivered to the mitochondria in cancer cells. Here we will briefly overview the mitochondria-targeted delivery strategies. In addition, the recent discovery of hot mitochondria in cancer cells and the development of mitochondrial temperature-responsive delivery systems for antitumor therapy will be reviewed.