Calcineurin signaling has been implicated in a broad spectrum of developmental processes in a variety of organ systems. Calcineurin is a calmodulin-dependent, calcium-activated protein phosphatase composed of catalytic and regulatory subunits. The serine/threonine-specific phosphatase functions within a signal transduction pathway that regulates gene expression and biological responses in many developmentally important cell types. Calcineurin signaling was first defined in T lymphocytes as a regulator of nuclear factor of activated T cells (NFAT) transcription factor nuclear translocation and activation. Recent studies have demonstrated the vital nature of calcium/calcineurin/NFAT signaling in cardiovascular and skeletal muscle development in vertebrates. Inhibition, mutation, or forced expression of calcineurin pathway genes result in defects or alterations in cardiomyocyte maturation, heart valve formation, vascular development, skeletal muscle differentiation and fiber-type switching, and cardiac and skeletal muscle hypertrophy. Conserved calcineurin genes are found in invertebrates such as Drosophila and Caenorhabditis elegans, and genetic studies have demonstrated specific myogenic functions for the phosphatase in their development. The ability to investigate calcineurin signaling pathways in vertebrates and model genetic organisms provides a great potential to more fully comprehend the functions of calcineurin and its interacting genes in heart, blood vessel, and muscle development.