The role of nuclear signaling in cancer biology has been studied extensively, from the elucidation of growth factor pathway activation, induction of cell motility and invasive responses, to the inhibition of cell death programs. However, if one is to consider such processes in the context of the complete cellular environment, the influences of cytosolic components should be considered as well. It is becoming more apparent that mitochondria may be the primary players in this putative “cytoplasmic influence” upon tumor cell behavior. In accordance with the endosymbiotic origin proposed for mitochondria and eukaryotic precursors, there exists a large amount of cross talk between mitochondrial- and nuclear-derived signals within the cell. For quite some time the understanding that the coordinated expression of both genomes is required for proper mitochondrial function has been realized, and our realization that such communication has the potential to regulate other critical cellular activities is growing. The mitochondrial genome is more susceptible to mutagenic events than nuclear DNA, suggesting that mtDNA alterations may represent an initial promoting factor for the onset of neoplasia. This effect might be related to changes in cell Ca2+ homeostasis, local redox balances, metabolic pathways, energy production, apoptotic potential or other uncharacterized signals which are controlled at least in part by the mitochondria. Of course, this is a simplistic model. The physiological expression of these putative relationships between mitochondrial signaling and cancer would certainly depend highly upon other variables such as the local cellular environment, level of cellular differentiation and tissue type, all of which are regulated by nuclear signals. The approach to future cancer therapies may include the specific targeting of mitochondria. Drastic changes to this organelle would affect both normal and cancerous tissues, therefore, only more subtle manipulation of mitochondrial functioning would be effective. The alteration of mitochondrial ATP generation, reactive oxygen species production, or sensitization to programmed cell death as an adjunct therapy used along with conventional cancer treatment strategies might enhance chemical or radiation efficacy and reduce the acquired tumor resistance to these agents. As a better understanding of specific mitochondrial signaling is obtained, the usefulness of any such clinical applications can be more appropriately assessed.