The p21 WAF1/Cip1 gene plays a central role in cell cycle regulation. Here we show that topoisomerase II inhibitors, genistein and etoposide, induce p21 WAF1/Cip1 expression mainly in a p53-dependent manner in human lung cancer cell line A549. However, although p53 accumulated, p21 WAF1/Cip1 expression did not depend on the level of Ser15 phosphorylation of p53. Caffeine, an ataxia telangiectasia-mutated (ATM), and ATM- and Rad3-related kinase (ATR) inhibitor, abrogated genistein-induced p21 WAF1/Cip1 and largely blocked etoposide-induced p21 WAF1/Cip1 expression. Wortmannin, an ATM- and DNA-dependent protein kinase inhibitor, partially inhibited p21 WAF1/Cip1 expression induced by genistein and etoposide, whereas UCN-01, a Chk1 inhibitor, partially blocked etoposide, but not genistein-induced p21 WAF1/Cip1 expression. These data suggest that both genistein and etoposide induce p21 WAF1/Cip1 expression in a p53-dependent manner. Genistein appears to stimulate p21 WAF1/Cip1 expression through p53 via ATM, whereas etoposide may activate both ATM and ATR pathways. Our results suggest different mechanisms participate in genistein and etoposide induced p21 WAF1/Cip1 expression.