Geminin interacts with a DNA replication initiation factor, Cdt1p, to suppress initiation of DNA replication in a Xenopus egg extract based cell-free system, leading to the expectation that the protein acts as an inhibitor of cell proliferation. Immunohistochemistry and immunoblotting for geminin, however, reveals that the protein is expressed specifically in proliferating lymphocytes and epithelial cells. This pattern is in contrast to the expression of a bona fide cell cycle inhibitor like p21/WAF1 that is specifically expressed in quiescent cells. Geminin is widely expressed in several malignancies and the number of geminin-expressing cells is directly proportional to the cell proliferation index as measured by Ki-67 expression. Therefore, instead of being a suppressor of cell proliferation, geminin expression is positively correlated with cell proliferation. Consistent with this observation, transient overexpression of wild-type geminin in cancer cells in culture did not produce a cell cycle block. A point mutation in the destruction box of geminin, however, results in a protein that is stabilized in G(1) and capable of arresting cells at the G(1)-S transition.