Thyrotropin-releasing hormone (TRH) acts via a G-protein-coupled receptor on lactotrophs to increase the intracellular free calcium ion concentration, [Ca(2+)](i). The [Ca(2+)](i) response depends on both TRH concentration and the duration of TRH exposure. An initial, short-lived [Ca(2+)](i) spike results from release of Ca(2+) from intracellular stores, whereas a later sustained [Ca(2+)](i) increase, often characterized by [Ca(2+)](i) oscillations, results from an influx of extracellular Ca(2+) through both voltage-gated and non-voltage-gated, store-operated Ca(2+) channels. The initial spike phase predominates at high doses of TRH, whereas the plateau phase predominates at low doses. The mechanisms underlying the complex [Ca(2+)](i) response to TRH are discussed.