Mitochondria undergo constant morphological changes through fusion, fission, and mitophagy. As the key organelle in cells, mitochondria are responsible for numerous essential cellular functions such as metabolism, regulation of calcium (Ca), generation of reactive oxygen species, and initiation of apoptosis. Unsurprisingly, mitochondrial dysfunctions underlie many pathologies including cancer. Currently, the gold standard for cancer treatment is chemotherapy, radiation, and surgery. However, the efficacy of these treatments varies across different cancer cells. It has been suggested that mitochondria may be at the center of these diverse responses. In the past decade, significant advances have been made in understanding distinct types of mitochondrial dysfunctions in cancer. Through investigations of underlying mechanisms, more effective treatment options are developed. We summarize various mitochondria dysfunctions in cancer progression that have led to the development of therapeutic options. Current mitochondrial-targeted therapies and challenges are discussed. To address the "root" of cancer, utilization of mitochondrial-targeted therapy to target cancer stem cells may be valuable. Investigation of other areas such as mitochondrial trafficking may offer new insights into cancer therapy. Moreover, common antibiotics could be explored as mitocans, and synthetic lethality screens can be utilized to overcome the plasticity of cancer cells.