AbstractDeregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular ener getics are associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, mitochondrial enzyme defects, oraltered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype.Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogen ase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 mightmodulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during onco genesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a processcalled retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca2þ, or oncometabolites are importantin the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellularmetabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a criticalrole in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promis ing strategy for the development of selective anticancer therapy.