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Cell differentiation is a fundamental biological event in which a precursor stem cell is turning into a specialized somatic cell. It is thus crucial for the development, tissue turnover and regeneration in mammals. Among the numerous changes taking place in a cell during a differentiation programme, the biology of mitochondria, the central organelle mainly responsible for energy homeostasis and stress adaptation, is deeply modified. These modifications are now well recognized as taking an active part to the completion of the differentiation programme. Indeed, mitochondrial biogenesis and metabolic shift are observed during cell differentiation, adapting many syntheses, calcium homeostasis, ATP and reactive oxygen species production, to the needs. These mitochondrial functions are substantially regulated by the post-translational modifications of the mitochondrial proteins among which lysine acetylation is essential. This mitoacetylome is then globally controlled by the balance between spontaneous/enzymatically-catalysed protein acetylation and the NAD+-dependent deacetylation mediated by Sirtuin 3. This enzyme is now considered as a major regulator of the function of the organelle. Regarding the requirement of these mitochondrial adaptations, the subsequent growing interest for this enzyme recently extended to the investigation of the mechanisms driving cell differentiation. This review summarizes the currently available information about the significance of SIRT3 in cell differentiation in physio-pathological contexts. We also suggest a control of the differentiation-activated autophagy by SIRT3, a hypothesis supported by recent findings establishing a causal link between SIRT3 and autophagy. Eventually, an update on the present pharmacological modulators of SIRT3 in a context of cell differentiation is discussed.