This study examined the response of PC-3 cells to physiological (0.5, 2.5, 5, 10 mu M) and pharmacological (50 mu M) concentrations of genistein which is a main bioactive compound in soy. Following 48 hr genistein treatment, cell-based assays and genome-wide microarray were performed. It was evidenced that maximal physiologically achievable concentrations of genistein (0.5-10 mu M) lead to significant increase in cell viability (p < 0.05) and decrease in migration at 0.5 mu M (p = 0.000) and 10 mu M (p = 0.001). The highest percentage of apoptotic cells was obtained at 50 mu M. Microarray analysis gave the most critical pathways such as cell cycle regulation and proliferation, tumorigenesis, DNA damage and repair, stress response, and apoptosis. Physiological concentrations (<= 10 mu M) induced activation of CDKs, MAPKs, and RPSKs, while high concentrations of genistein (>10 mu M) appeared to have a novel mechanism of action, specifically down-regulating TGF-beta by decreasing specifically SMAD 2/3,4 which are in the downstream TGF-beta signaling cascade. Practical applications This study highlights for the first time that maximal physiologically achievable concentrations of genistein (0.5-10 mu M) have proliferative effects evidenced by alterations in global gene expression patterns of PC-3 cells. Our results particularly represent a closer examination of dietary genistein consumption for the prevention and/or treatment of cancer that maximal physiologically achievable concentrations of genistein could have detrimental effects on individuals with prostate cancer. Further studies as in vivo would be necessary to remove shadows on the effect of genistein on prostate cancer progression.