It has long been clear that mitochondria play important roles in metastatic disease, including regulatory contributions. Nonetheless, our knowledge in this area was too fragmentary to be of practical clinical use. However, over the last decade a robust community of investigators has extended our knowledge such that it is practical to begin to build testable theories. Moreover, these theories can plausibly give clinicians actionable opportunities to effectively attack advanced, currently treatment-resistant carcinomas. Our goal here is to contextualize and review important features of this recent new data base. We will also illustrate the kind of testable speculative theories that might be built on this foundation. Specifically, we will explore the evidence that many or most advanced, treatment-resistant tumors converge on a uniform state in which mitochondria play a universal, indispensable regulatory role (Figure 1 [1]). Speculative hypotheses of this form are robustly testable/falsifiable. Moreover, such theories suggest a specific novel approach to clinical attack on advanced, currently treatment-resistant carcinomas.