Inositol 1,4,5-trisphosphate receptors (IP(3)R) within the endoplasmic reticulum mediate release of Ca(2+) from intracellular stores. Different channels usually mediate Ca(2+) entry across the plasma membrane. In B lymphocytes and a cell line derived from them (DT40 cells), very few functional IP(3)R (approximately 2/cell) are invariably expressed in the plasma membrane, where they mediate about half the Ca(2+) entry evoked by activation of the B-cell receptor. We show that cells reliably count approximately 2 functional IP(3)R into the plasma membrane even when their conductance and ability to bind IP(3) are massively attenuated. We conclude that very small numbers of functional IP(3)R can be reliably counted into a specific membrane compartment in the absence of feedback signals from the active protein.