The decision of a cell to divide, differentiate or die is dependent on the coupling of cytoplasmic signals to the activation and repression of specific sets of genes in the nucleus. Many of the signal transduction pathways that control these cellular decisions are activated by elevation of intracellular calcium. Recent studies have revealed a central role for the myocyte enhancer factor-2 (MEF2) family of transcription factors in linking calcium-dependent signaling pathways to the genes responsible for cell division, differentiation and death. This article describes the post-translational mechanisms that confer calcium-sensitivity to MEF2 and its downstream target genes, and considers how this transcription factor can control diverse and mutually exclusive cellular decisions.