Mast cell development is a complex process that results in the appearance of phenotypically distinct populations of mast cells in different anatomical sites. Mice homozygous for mutations at the W or S1 locus exhibit several phenotypic abnormalities, including a virtual absence of mast cells in all organs and tissues. Recent work indicates that W encodes the c-kit tyrosine kinase receptor, whereas S1 encodes a c-kit ligand that we have designated stem cell factor (SCF). Recombinant or purified natural forms of the c-kit ligand induce proliferation of certain mast cell populations in vitro, and injection of recombinant SCF permits mast cells to develop in mast cell-deficient WCB6F1-S1/S1d mice. However, the effects of SCF on mast cell proliferation, maturation, and phenotype in normal mice in vivo were not investigated. We now report that local administration of SCF in vivo promotes the development of connective tissue-type mast cells (CTMC) in the skin of mice and that systemic administration of SCF induces the development of both CTMC and mucosal mast cells (MMC) in rats. Rats treated with SCF also develop significantly increased tissue levels of specific rat mast cell proteases (RMCP) characteristic of either CTMC (RMCP I) or MMC (RMCP II). These findings demonstrate that SCF can induce the expansion of both CTMC and MMC populations in vivo and show that SCF can regulate at least one cellular lineage that expresses c-kit, the mast cell, through complex effects on proliferation and maturation.