Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Mitochondria contribute to bioenergetics, metabolism, biosynthesis, and cell death or survival functions in host cells. Reactive oxygen species (ROS) generated by mitochondria participate in stress signaling in normal cells but also contribute to the initiation of nuclear or mitochondrial DNA mutations that promote neoplastic transformation. In cancer cells, mitochondrial ROS amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations that lead to metastatic behavior. Mitochondria perform important functions in normal cells, so disabling their function is not a feasible therapy for cancer. However, ROS signaling contributes to proliferation and survival in many cancers, so targeting mitochondria-to-cell redox communication represents a promising avenue for future therapy. Mitochondria and host cells have a symbiotic relationship that began approximately 2 billion years ago. This relationship evolved over time, with gene transfer from the endosymbiont to the nucleus. The original symbiotic relationship succeeded due to mutual benefits from complementary roles in cellular energy production. Mitochondria perform oxidative phosphorylation, which is likely the principal benefit for the host cell. In exchange, the antecedent mitochondria enjoyed an intracellular environment rich in nutrients and protected from extremes of pH that could undermine their membrane transport functions. Mitochondria also facilitate cellular stress responses, including the response to hypoxia and the activation of programmed cell death via the release of pro-apoptotic molecules from the intermembrane space (IMS) to the cytosol. Under normal conditions, mitochondria trigger redox signaling in the cell through the release of reactive oxygen species (ROS) from the electron transport chain (ETC). Under pathophysiological conditions, ROS generation from mitochondria can contribute to the initiation of cancer and to an amplification of the tumour cell phenotype. At the same time, mitochondrial ROS may render the tumour cell vulnerable to therapies that further stress their ability to regulate redox homeostasis, thereby opening opportunities for novel therapies. ROS are generated in various sites within mitochondria, including the tricarboxylic acid cycle (TCA cycle), the electron transport chain (ETC), and other enzymatic complexes. These ROS can contribute to the transformation of healthy cells into tumours and amplify the phenotypic behavior in terms of proliferation, survival, and migration. Tumour cells rely on increased mitochondrial ROS signalling to regulate their phenotype, but this characteristic puts them in dangerous territory in terms of their vulnerability to therapeutic interventions that further stress their redox homeostasis. Mitochondrial DNA (mtDNA) is a target of ROS in cancer, as mutations in mtDNA seem to be capable of promoting tumorigenesis. mtDNA mutations can contribute to the generation of ROS in cancer, which can further promote tumorigenesis. Mitochondrial ROS also contribute to genomic instability, which can lead to additional mutations and tumorigenesis.Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Mitochondria contribute to bioenergetics, metabolism, biosynthesis, and cell death or survival functions in host cells. Reactive oxygen species (ROS) generated by mitochondria participate in stress signaling in normal cells but also contribute to the initiation of nuclear or mitochondrial DNA mutations that promote neoplastic transformation. In cancer cells, mitochondrial ROS amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations that lead to metastatic behavior. Mitochondria perform important functions in normal cells, so disabling their function is not a feasible therapy for cancer. However, ROS signaling contributes to proliferation and survival in many cancers, so targeting mitochondria-to-cell redox communication represents a promising avenue for future therapy. Mitochondria and host cells have a symbiotic relationship that began approximately 2 billion years ago. This relationship evolved over time, with gene transfer from the endosymbiont to the nucleus. The original symbiotic relationship succeeded due to mutual benefits from complementary roles in cellular energy production. Mitochondria perform oxidative phosphorylation, which is likely the principal benefit for the host cell. In exchange, the antecedent mitochondria enjoyed an intracellular environment rich in nutrients and protected from extremes of pH that could undermine their membrane transport functions. Mitochondria also facilitate cellular stress responses, including the response to hypoxia and the activation of programmed cell death via the release of pro-apoptotic molecules from the intermembrane space (IMS) to the cytosol. Under normal conditions, mitochondria trigger redox signaling in the cell through the release of reactive oxygen species (ROS) from the electron transport chain (ETC). Under pathophysiological conditions, ROS generation from mitochondria can contribute to the initiation of cancer and to an amplification of the tumour cell phenotype. At the same time, mitochondrial ROS may render the tumour cell vulnerable to therapies that further stress their ability to regulate redox homeostasis, thereby opening opportunities for novel therapies. ROS are generated in various sites within mitochondria, including the tricarboxylic acid cycle (TCA cycle), the electron transport chain (ETC), and other enzymatic complexes. These ROS can contribute to the transformation of healthy cells into tumours and amplify the phenotypic behavior in terms of proliferation, survival, and migration. Tumour cells rely on increased mitochondrial ROS signalling to regulate their phenotype, but this characteristic puts them in dangerous territory in terms of their vulnerability to therapeutic interventions that further stress their redox homeostasis. Mitochondrial DNA (mtDNA) is a target of ROS in cancer, as mutations in mtDNA seem to be capable of promoting tumorigenesis. mtDNA mutations can contribute to the generation of ROS in cancer, which can further promote tumorigenesis. Mitochondrial ROS also contribute to genomic instability, which can lead to additional mutations and tumorigenesis.