Mast cells depleted of cellular calcium (Ca) by a 3 hr exposure to Ca-free conditions and then bathed in Ca-free Locke failed to release histamine when stimulated by compound 48/80 or peptides. The cellular Ca required for histamine release could be replenished by a 5 sec exposure to extracellular Ca at 37 degrees C. To inhibit this replenished cellular Ca dependent histamine secretion required an additional 3 hr exposure to Ca-free conditions. When cellular Ca was replenished at 4 degrees C, an additional 2 min incubation at 37 degrees C was required to restore stimulated secretion to a maximum. During this 2 min incubation period the replenished cellular Ca is suggested to be "processed" so that it can be used for secretion. Manganese (Mn) or cobalt added during (but not after) this 2 min incubation period prevented the restoration of histamine release. Preincubation of cellular Ca depleted mast cells in Mn (0.1-1 mM) blocked the effect of subsequent Ca replenishment at 37 degrees C while cobalt and barium were less inhibitory. Neither magnesium nor strontium were inhibitory. Extracellular sodium (Na) was required for the restoration of cellular Ca dependent histamine secretion. Lithium could substitute for Na but rubidium and potassium were ineffective.