An increasing number of human diseases are thought to relate to disturbances in metal ion homeostasis, including metal ion overload and deficiency disorders, and neurodegenerative diseases. Recently, it was reported that copper treatment of hepatocytes results in induction of apoptosis during the course of hepatic failure in acute Wilson’s disease. The levels of metal ions might be important factors in controlling the activities of microsomal monooxygenases, which are crucial enzymes in the metabolism of drugs, steroids, and carcinogens in eukaryotes. This enzyme system includes cytochrome P450 (CYP), NADPH-CYP reductase (NPR), and phospholipids. The possible role of metal ions in modulating the conformation and catalytic function of CYPs and NPR and how these functional changes correlate with structural changes are discussed. It is proposed that metals ions can modulate the  CYP activities by changing the conformation, and that the balance of metal ions present in the cytosol is important for a functional conformation of CYPs in a monooxygenase system including NPR.