Brief episodes of ischemia protect or "precondition" the heart and reduce infarct size caused by a subsequent sustained ischemic insult. Despite a decade of intensive investigation, the cellular mechanism(s) responsible for this paradoxical protection remain poorly understood. In this review, we focus on the emerging concept that alterations in intracellular calcium homeostasis may participate in either triggering and/or mediating infarct size reduction with preconditioning.