The AMP-activated protein kinase (AMPK) system, an evolutionary conserved low-energy checkpoint, functions as a canonical suppressor of cell proliferation. Proliferating cells, however, should also ensure a proper spatio-temporal bond between AMPK-sensed cell's metabolic status and cell division. A crucial linkage between cell proliferation and AMPK-interpreted cell bioenergetics appears to take place during the M-phase of the cell cycle. A recent description of a physical interplay between the active form the alpha-catalytic AMPK subunit with essential mitotic regulators in the centrosome and midbody has provided direct evidence that tumor-suppressive properties for AMPK closely relate to its ability to exquisitely coordinate sensing of energy resources and the fundamental biological process of genome division during mitosis and cytokinesis. Based on recent findings in our laboratory observing abortive cytokinesis followed by nuclear shape reorganization, mitotic catastrophe, polyploidization events, and cell giantism in p53-null cancer cells pharmacologically manipulated to exhibit sustained activation of AMPK, we now propose that AMPK is a novel and biologically significant participant with a tumor suppressive activity in the mitotic/cytokinetic phase of the cell cycle. In this scenario, molecular co-evolution of the energy-sensing cytokinetic tumor suppressor AMPK within the chronic biophysical constraints of the tumor microenvironment may inherently promote a continuous generation of structural and numerical changes in chromosomes favoring generation of nascent tumor cells and/or tumor-initiating cells over tumor cell death.