Thapsigargin is the most widely used inhibitor of the ubiquitous sarco- endoplasmic reticulum Ca²⁺-ATPases in mammalian cells. Over the past ten years, this guaianolide compound of plant origin has become a popular tool in a host of studies directed at elucidating the mechanisms of intracellular Ca²⁺ signalling. Its remarkable potency and selectivity have been instrumental in widening our view of the function of intracellular Ca²⁺ stores to include such key aspects as store-operated Ca²⁺ entry or the involvement of the stores in protein synthesis or cell growth. In this article Marek Treiman, Casper Caspersen and Soren Brogger Christensen review the key pharmacological features of thapsigargin action; they also discuss some of the ways in which its unique properties have shown to be important for obtaining new insights into the biology of Ca²⁺ stores, and how these properties might encompass a therapeutic potential. In parallel, attention is drawn to some of the limitations and pitfalls encountered when working with thapsigargin.