Cancer is an intricate web of diseases marked by the uncontrolled proliferation of abnormal cells. At its core lies the complex interplay of genes, where inherited mutations or environmental factors lead to genetic aberrations that initiate and drive cancer progression. Each cancer type, from the silent progression of pancreatic cancer to systemic impacts of leukemia, presents unique challenges, necessitating tailored approaches for diagnosis and treatment. A key aspect of cancer biology is the role of mitochondria, the cell’s powerhouses. These organelles are central to various cellular functions, especially energy production through oxidative phosphorylation. Mitochondrial dysfunction, caused by disrupted calcium regulation or altered metabolic pathways, plays a significant role in cancer development and progression. For instance, mitochondrial calcium dysregulation contributes to tumor cell survival and growth. The mitochondrial genome (mtDNA) is highly susceptible to mutations due to increased ROS production and limited repair mechanisms. These mutations significantly impact cancer development and progression. The review provides an in-depth analysis of mutations in mitochondrial protein-coding genes (PCGs) across the different mitochondrial complexes, highlighting the variability in mutation rates and impacts among various cancer types. It also discusses the roles of mitochondrial tRNA and rRNA gene mutations in cancer development. These mutations, while not as drastic as those in PCGs, still contribute significantly to the oncogenic process. Furthermore, the review touches upon the potential of anticancer agents known as mitocans, which target mitochondrial metabolic and apoptotic pathways. These agents not only offer novel therapeutic strategies, but may also become cellular targets for future cancer therapies. The medical community eagerly anticipates the results of clinical trials involving these agents. Here, we emphasize the critical role of mtDNA mutations in cancer. This comprehensive understanding could lead to new therapeutic targets and strategies, advancing the fight against cancer.