Metastatic progression of cancer is associated with poor outcome, and here we examine metabolic changes underlying this process. Although aerobic glycolysis is known to promote metastasis, we have now identified a different switch primarily affecting mitochondria. The switch involves overload of the electron transport chain (ETC) with preserved mitochondrial functions but increased mitochondrial superoxide production. It provides a metastatic advantage phenocopied by partial ETC inhibition, another situation associated with enhanced superoxide production. Both cases involved protein tyrosine kinases Src and Pyk2 as downstream effectors. Thus, two different events, ETC overload and partial ETC inhibition, promote superoxide-dependent tumor cell migration, invasion, clonogenicity, and metastasis. Consequently, specific scavenging of mitochondrial superoxide with mitoTEMPO blocked tumor cell migration and prevented spontaneous tumor metastasis in murine and human tumor models. Cancer is a leading cause of death worldwide and metastatic progression is associated with poor outcome. Porporato etal. have identified a metabolic switch that allows tumor cell mitochondria to drive successful metastatic progression. At the dissemination stage, some metastatic progenitor cells undergo a mitochondrial overload, whereas others experience a moderate respiration dysfunction. Both events promote superoxide-dependent metastasis. Consequently, mitochondria-specific superoxide scavenging inhibits metastatic dissemination, which opens a new avenue for therapeutic prevention.