The regulation of tissue mast cell number depends both on the rate of production of mast cell precursors and the length of survival of mature mast cells within tissues. Once mast cell precursors target to tissues, their survival may largely be dependent upon the local production of stem cell factor (SCF). Withdrawal of interleukin (IL)-3 results in mast cell apoptosis. The apoptotic changes following IL-3 deprivation are prevented by the addition of SCF which exerts its rescue effect upon interaction with its c-Kit tyrosine kinase receptor. Mast cells undergo apoptosis on withdrawal of IL-3 coincident with a decrease in endogenous bcl-2 mRNA; however, SCF does not induce expression of bcl-2 when added to these cells. When overexpressed, bcl-2 prolongs survival of bcl-2-transfected mast cells following IL-3 deprivation. Transforming growth factor-beta was found to specifically prevent this SCF-mediated rescue from apoptosis, probably by down-regulating the expression of c-Kit. Thus, microenvironmental factors play an important role in regulating mast cell numbers by effecting survival in the periphery.