Cellular events correlated to the histamine release process were studied in rat peritoneal mast cells applying the dye toluidine blue as histamine-discharging agent. The effects of toluidine blue were studied both in the presence and absence of calcium. Histamine release was clearly dose-dependent within the range 2X10––5 m toluidine blue to 4X10––4 m. Whereas spontaneous histamine release values were in the order of a few percent, maximum release in the presence of calcium amounted to 65–80%. Histamine release was accompanied by characteristic morphologic changes in the cells: granule fine structure was markedly altered, perigranular vacuoles were formed and, through repeated fusions of the vacuole-delimiting membranes, large caveolae containing granule matrices arose. In fortuitous sections, these cavities were seen to communicate with the extracellular space through pores, often of substantial size. Granule extrusion from the cellular domain to the surrounding medium, although it did occur to a certain extent, was not a prominent feature of the histamine release process. The dose-response curve for histamine release was lowered by roughly one half in the absence of calcium. This was reflected in mast cell morphology by a decreased tendency towards granule alteration and vacuole formation. The present observations are viewed in the light of various suggested models for the mode of histamine release from mast cells.