Genistein, a natural flavone compound, has been proposed to be responsible for the lower rate of breast cancer in Asian women. The cellular mechanisms of genistein's inhibition of breast cancer progression are largely unknown. In a previous study our laboratory has presented evidence that genistein inhibits cell proliferation of breast carcinoma cells, an inhibition which is associated with a specific G2/M arrest, induction of p21WAF/CIP1 expression and apoptosis. In the present study, we present experimental evidence that illustrates that the actions of genistein are not limited to anti-proliferation: we show that genistein can inhibit both constitutive as well as epidermal growth factor (EGF)-stimulated invasion in estrogen receptor (ER)-negative human breast carcinoma lines, MDA-MB-231 and MDA-MB-468. This inhibition is characterized by the down regulation of MMP-9 (92 kDa type IV collagenase) and up regulation of TIMP-1 (tissue inhibitor of metalloproteinases) and the trypsin inhibitors: protease nexin-II (PN-II) and alpha 1-antitrypsin (alpha 1-AT). The in vivo actions of genistein may therefore extend beyond those traditionally implicated in chemoprevention, e.g., antiproliferation; genistein may act in vivo by blocking additional stages of breast cancer progression such as those stages resulting in invasion and metastasis.