Physiological studies have established the role of plant high-capacity vacuolar H+/Ca2+ exchange activity in ion homeostasis and signal transduction. The molecular characterization and structure-function analyses of these transporters are just beginning to emerge. In yeast, Ca2+ signaling molecules regulate vacuolar H+/Ca2+ exchange. Recently, some of the Ca2+ dependent "molecular relay" molecules have been characterized in plants; however, the regulation of plant vacuolar H+/Ca2+ exchange remains an open question.