Mitochondrial shape change, brought about by molecules that promote either fission or fusion between individual mitochondria, has been documented in several model systems. However, the deeper significance of mitochondrial shape change has only recently begun to emerge: among others, it appears to play a role in the regulation of cell proliferation. Here, I review the emerging interplay between mitochondrial fission-fusion components with cell cycle regulatory machineries and how that may impact cell differentiation. Regulation of mitochondrial shape may modulate mitochondrial metabolism and/or energetics to promote crosstalk between signaling components and the cell cycle machinery. Focused research in this area will reveal the exact role of mitochondria in development and disease, specifically in stem cell regulation and tumorigenesis. Such research may also reveal whether and how the endosymbiotic event that gave rise to the mitochondrion was crucial for the evolution of cell cycle regulatory mechanisms in eukaryotes that are absent in prokaryotes. © 2013 WILEY Periodicals, Inc.