In breast cancer, proliferative activity represents one of the biologic processes most thoroughly investigated for its association with tumor progression. In addition to the mitotic activity component of pathologic grading systems, several proliferation indices have provided independent information on prognosis and response to specific treatments in large retrospective studies. Recently, results from treatment protocols prospectively planned to test the clinical utility of proliferative activity have indicated that tumor cell proliferation markers identify two subsets among patients with lymph node-negative cancers: 1) those at a very low risk of relapse and 2) those who will benefit from regimens including antimetabolites. Future efforts should compare the prognostic accuracy of different proliferation markers, confirm preliminary evidence of a relationship between proliferation and response to specific systemic treatments, and standardize assay techniques to facilitate their transfer to general oncology practice.