It is proposed that volatile anesthetics act through the modification of Ca2+ homeostasis in excitable cells. To test this hypothesis, cardiac and skeletal muscles were used as models to examine Ca2+ response, and Ca2+ regulatory and delivery mechanisms. I found that halothane did not alter Ca2+ binding to cardiac troponin C. However, halothane and isoflurane reversibly decreased the Ca2+ affinity of calmodulin at low anesthetic concentration, and irreversibly increased the Ca2+ affinity of calmodulin at high anesthetic concentration. The volatile anesthetics also increased the permeability of light fraction of sarcoplasmic reticulum (SR) to Ca2+. I conclude that volatile anesthetics alter calcium homeostasis in cardiac and skeletal muscles. This work was in part performed in collaboration with Giovanni Salviati and the author benefited from Salviati's work in similar areas.