Mitochondria are a major focus of research in cancer due to their critical role in tumor physiology and metabolism. Metabolic remodeling is observed in tumor cells, often resulting in increased glycolytic activity, which serves for the generation of adenosine triphosphate (ATP), and as hubs for biosynthesis of key metabolites essential for cancer cell growth and proliferation. Mitochondria, thus, appear as a critical nexus in cancer metabolic alterations. Not only increased overexpression of oncogenes leads to altered mitochondrial respiration due to remodeling of mitochondrial gene expression and substrate channeling, but also particular mutations in components of the respiratory chain trigger an upstream feedback mechanism which also leads to metabolic reshaping in cancer cells. Mitochondrial respiration can thus be controlled by intrinsic and extrinsic mechanisms in cancer cells, which ultimately translates into different abilities to generate mitochondrial ATP. Altered mitochondrial structures and processes can be a target for chemotherapeutics, which are increasingly being developed to specifically target mitochondria in tumors. The present chapter reviews current knowledge on regulation of mitochondrial respiration and overall metabolism and how these specific alterations in the cell powerhouse can be used to eliminate tumors.