Cancer cells continuously adapt to their local and external milieu during their growth by acquiring new biochemical and cellular properties. For example, in many cancer cells, glycolytic capacity increases even in non-hypoxic conditions. The latter phenomenon is known as ‘aerobic glycolysis’ and has become a central topic in the field of cancer biology. Aerobic glycolysis is induced by several factors including dysfunction of mitochondria. The cells with the dysfunction of the oxidative phosphorylation (OXPHOS) increase production of reactive oxygen species (ROS) that can activate some signaling proteins and induce mutations in oncogenes and tumor suppressor genes. Dysfunction of the enzymes in the Krebs cycle may impact activity of transcription factors such as HIF1α through changes in the amount of the organic acids in the cycle. Study of the mitochondria function also reveals important insights on JmjC-domain proteins, which demethylate histones and therefore control gene expression. The oncogene myc, which is widely overexpressed in cancer cells, induces the expression of genes involved in mitochondrial ATP production. Collectively, there is emerging evidence supporting the idea that the machinery involved in mitochondrial ATP production can serve as a ‘pathway target’ for development of diagnostic tests to evaluate behaviors of human cancers, and to identify novel drug targets that may be critical for treatment of molecular subtypes of cancers. This expert review presents a synthesis of the recent advances in our understanding of the mitochondrial dysfunction and ATP production, and ways in which this knowledge may translate into personalized cancer therapeutics and diagnostic tests.