Compound 48/80-induced histamine release may utilize both intracellular and extracellular calcium. The release is inhibited by La3+ and TMB-8 both in the presence and absence of calcium. The observations are consistent with a mobilization of calcium from the inner surface of the plasma membrane supporting the release. TMB-8 probably acts at more than one site. It has been shown to inhibit skeletal muscle contraction and this has been correlated to its inhibitory effect on the release of Ca2+ from the sarcoplasmic reticulum. TMB-8 also inhibits resting cellular influx and efflux of calcium in the ileum. Anaphylactic and dextran-induced histamine release is dependent on extracellular calcium; the inhibition of the release by TMB-8 seems to be primarily due to an interference with calcium transport across the plasma membrane. In the absence of extracellular calcium the inhibition of compound 48/80-induced histamine release by TMB-8 seems to be due to stabilization of Ca2+ binding to cellular stores.