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Exciting new studies are increasingly strengthening the link between mitochondrial mutagenesis and tumor progression. Here we provide a comprehensive review and meta-analysis of studies reporting on mitochondrial DNA mutations in common human cancers. We discuss possible mechanisms by which mitochondrial DNA mutations may influence carcinogenesis, outline important caveats for interpreting the detected mutations—particularly differentiating causality from association-and suggest how new mutational assays may help resolve fundamental controversies in the field and delineate the origin and expansion of neoplastic cell lineages. Finally, we discuss the potential clinical utility of mtDNA mutations for improving the sensitivity of early cancer diagnosis, rapidly detecting cancer recurrence, and predicting the disease outcome. Environ. Mol. Mutagen. 51:427-439, 2010.