Calcium ions are ubiquitous intracellular mediators of numerous cellular processes. One of the main mechanisms of Ca2+ entry into the cell involves the opening of Ca2+ channels in the plasma membrane. To effectively control Ca2+ signalling, Ca2+ channels inactivate rapidly by a mechanism that depends on an elevation of intracellular Ca2+ within tens of nanometres of the channel pore. A structural understanding of this mechanism will provide a framework for understanding the regulation of Ca2+ entry and accumulation in neurons. Recent physiological, biochemical and molecular studies have yielded new insights into the regulation of neuronal Ca2+ channels.