Caspases, which comprise a family of cysteine proteases, are best known for their central role in apoptosis. Evidence suggests, however, that caspase-3 – an effector caspase that, when activated, cleaves numerous intracellular proteins during apoptosis – is also necessary for the differentiation of muscle progenitor cells into myofibres. To determine how such disparate roles can be reconciled, Howard Fearnhead and colleagues (p. 3786) ask how caspase-3 activity is regulated during muscle differentiation. Using the C2C12 mouse myoblast cell line, the authors show that caspase-9 – which activates caspase-3 during the mitochondria-dependent apoptotic pathway – is activated during myotube formation. Moreover, knocking down caspase-9 expression strongly decreases both myoblast fusion and caspase-3 activation. The authors demonstrate that overexpression of Bcl-xL, which inhibits caspase-9 activation during apoptosis by preserving mitochondrial outer-membrane integrity, also inhibits myoblast fusion; counterintuitively, however, no depolarisation of the outer membrane is observed during C2C12 differentiation. Thus, caspase-9 appears to promote muscle differentiation – but it might, the authors propose, be activated by a mechanism that is not dependent on mitochondria.