Lithium salts have been in use for the treatment of bipolar disorder for more than 50 years, but their pharmacological mode of action remains a matter of conjecture. Li(+) and Mg(2+) share many physicochemical properties. Not surprisingly, many reported cellular targets for Li(+) action involve Mg(2+)-activated enzymes, which are inhibited by Li(+). In this Account, we describe results from our and other laboratories that suggest that a competition mechanism between Li(+) and Mg(2+) ions for Mg(2+)-binding sites in cellular components is the underlying theme in putative mechanisms of Li(+) action.