Mitochondrial DNA (mtDNA) encodes for only a fraction of the proteins that are encoded within the nucleus, and therefore has typically been regarded as a lesser player in cancer biology and metastasis. Accumulating evidence, however, supports an increased role for mtDNA impacting tumor progression and metastatic susceptibility. Unfortunately, due to this delay, there is a dearth of data defining the relative contributions of specific mtDNA polymorphisms (SNP), which leads to an inability to effectively use these polymorphisms to guide and enhance therapeutic strategies and diagnosis. In addition, evidence also suggests that differences in mtDNA impact not only the cancer cells but also the cells within the surrounding tumor microenvironment, suggesting a broad encompassing role for mtDNA polymorphisms in regulating the disease progression. mtDNA may have profound implications in the regulation of cancer biology and metastasis. However, there are still great lengths to go to understand fully its contributions. Thus, herein, we discuss the recent advances in our understanding of mtDNA in cancer and metastasis, providing a framework for future functional validation and discovery.