c-Kit has been shown to be mutated in several types of tumours, and its activity has been correlated with increased proliferation rates in a subset of multiple myeloma (MM) patients. We have investigated the effect of imatinib mesylate (STI571), an inhibitor of c-Kit, on MM cells. STI571 inhibited the proliferation of MM cells by arresting cell cycle progression. Western blotting of cell cycle proteins showed that STI571 increased the levels of p21 and p16. MM cells expressed abl, but its level of tyrosine phosphorylation was low and unaffected by treatment with STI571. c-Kit was also expressed in certain MM cell lines, and its phosphorylation was stimulated by stem cell factor. However, the failure to detect the receptor protein in other MM cell lines in which cell proliferation was inhibited by STI571 suggests that its effect on these c-Kit-negative MM cell lines might be caused by the action of the drug on yet unknown targets. STI571 inhibited the proliferation of MM cells resistant to dexamethasone or melphalan and had an additive effect when combined with dexamethasone. Efforts to understand the action of STI571 in MM cells may help to identify these potentially useful targets in the treatment of this and other disorders.