Ca²⁺ signaling plays a central role in hypertrophic growth of cardiac and skeletal muscle in response to mechanical load and a variety of signals. However, the mechanisms whereby alterations in Ca²⁺ in the cytoplasm activate the hypertrophic response and result in longterm changes in muscle gene expression are unclear. The Ca²⁺, calmodulin‐dependent protein phosphatase calcineurin has been proposed to control cardiac and skeletal muscle hypertrophy by acting as a Ca²⁺ sensor that couples prolonged changes in Ca²⁺ levels to reprogramming of muscle gene expression. Calcineurin also controls the contractile and metabolic properties of skeletal muscle by activating the slow muscle fiber‐specific gene program, which is dependent on Ca²⁺ signaling. Transcription factors of the NFAT and MEF2 families serve as endpoints for the signaling pathways whereby calcineurin controls muscle hypertrophy and fiber‐type. We consider these findings in the context of a model for Ca²⁺‐regulated gene expression in muscle cells and discuss potential implications of these findings for pharmacologic modification of cardiac and skeletal muscle function. BioEssays 22:510–519, 2000. © 2000 John Wiley & Sons, Inc.