During mammalian development, electrical activity promotes the calcium- dependent survival of neurons that have made appropriate synaptic connections. However, the mechanisms by which calcium mediates neuronal survival during development are not well characterized. A transcription- dependent mechanism was identified by which calcium influx into neurons promoted cell survival. The transcription factor MEF2 was selectively expressed in newly generated postmitotic neurons and was required for the survival of these neurons. Calcium influx into cerebellar granule neurons led to activation of p38 mitogen-activated protein kinase-dependent phosphorylation and activation of MEF2. Once activated, MEF2 regulated neuronal survival by stimulating MEF2-dependent gene transcription. These findings demonstrate that MEF2 is a calcium-regulated transcription factor and define a function for MEF2 during nervous system development that is distinct from previously well-characterized functions of MEF2 during muscle differentiation.