This review summarizes current knowledge concerning structure-function, substrate specificity, localization, and regulatory properties of calcineurin. Calcineurin is composed of two nonidentical subunits, one of which is responsible for catalytic activity and calmodulin binding while the other subunit contains four high-affinity Ca2+-binding sites. The enzyme possesses calmodulin-stimulated and metal ion-dependent phosphatase activity toward several nonprotein and phosphoseryl-, phosphothreonyl- and phosphotyrosyl-containing protein substrates. These recent results suggest that the protein may play a multifunctional role in interactions between the Ca2+/CaM second messenger system and other second messenger systems.