The Stat3 transcription factor is hyperactive in various types of cancer, and thus the regulation of its nuclear activities has been well studied. However, Stat3 also acts within the mitochondria, but its functions within this compartment remain incompletely understood. In their work, Francesco Argenton and colleagues reveal how mitochondrial Stat3 affects proliferation of stem cells in zebrafish. They show that mitochondrially targeted Stat3 can drive the expression of mitochondrial genes and the proliferation marker pcna in the peripheral midbrain layer of zebrafish embryos. Interestingly, the Stat3 DNA-binding domain is dispensable for mitochondrial DNA (mtDNA) transcription. In contrast, a non-phosphorylatable mutant of either Y705, which retains transcriptional activity but does not localise correctly within mitochondria, or S727 in Stat3 prevents its action on mtDNA. Similarly, preventing the phosphorylation of Y705 and S727 by inhibiting the kinases targeting these residues – JAK and MEK, respectively – interferes with Stat3-mediated mtDNA transcription and cell proliferation. Moreover, the authors show that Stat3 is required for cell proliferation in both the brain and the intestine. Collectively, these results suggest that a non-canonical function of Stat3 on mtDNA could regulate cell proliferation. If this pathway were to play an important role in tumourigenesis, it would open the door to the development of novel cancer therapeutics.