Oscillations in the cytosolic free Ca2+ concentration ([Ca2+]i) have been described in a variety of cells. In some cases, [Ca2+]i oscillations reflect cycles of membrane depolarization and voltage-dependent Ca2+ entry. In others, they are caused by periodic Ca2+ uptake and release by internal stores, with little immediate requirement for external Ca2+. A third type of [Ca2+]i oscillation is typified by caffeine-induced oscillations in sympathetic neurons. Here, the oscillations depend on the interplay between Ca2+ transport across the plasma membrane and transport by a caffeine-sensitive store. These oscillations can occur at a steady membrane potential and are blocked by ryanodine (1 microM), indicating that they do not result from voltage-dependent changes in Ca2+ entry but do require Ca(2+)-induced Ca2+ release. Entry of Ca2+ from the external medium is important during all phases of the oscillatory cycle except the rapid upstroke, which is dominated by Ca2+ release from an internal store. It is proposed that caffeine-induced [Ca2+]i oscillations are cyclic perturbations of [Ca2+]i caused by exchange of Ca2+ between the cytosol and the caffeine-sensitive store: net Ca2+ loss from the store increases [Ca2+]i transiently above its steady-state value ([Ca2+]ss), whereas net accumulation of Ca2+ by the store transiently depresses [Ca2+]i below [Ca2+]ss. The effects of rapid removal of Ca2+ and caffeine on the rate of change of [Ca2+]i (d[Ca2+]i/dt) provide estimates of the rates of net Ca2+ entry and (caffeine-sensitive) Ca2+ release and information on the way these rates vary during the oscillatory cycle.