Abstract Murine intraepithelial lymphocytes (IEL) express c-kit, the receptor for stem cell factor (SCF). SCF induced a low but significant proliferative response in IEL, but not in splenic T cells. SCF stimulation of IEL resulted in an expansion of the c-kit +, TCRγδ +cell population. SCF-induced proliferation was dependent upon SCF–c-kit interactions, since antibody to c-kit blocked this response, and IEL obtained from c-kit mutant (W/W v) mice failed to respond to SCF. SCF acted synergistically with anti-TCRγδ and with concavalin A (Con A) to induce proliferation and interferon γ (IFN-γ) production in IEL. Finally, mice injected with SCF had a significant increase in the number of IEL in the small intestine. SCF-treated mice had increased numbers of TCRαβ +and TCRγδ +cell populations, as well as increased numbers of c-kit +and c-kit −IEL. These data suggest that SCF–c-kit interactions play an important role in regulating IEL expansion and activation.