Isoliquiritigenin is a natural flavonoid isolated from licorice, shallot and bean sprouts. The effect of isoliquiritigenin on cell proliferation and cell cycle progression was examined in the A549 human lung cancer cell line. Isoliquiritigenin significantly inhibited the proliferation of lung cancer cells in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that isoliquiritigenin restrained the cell cycle progression at G2/M phase. Further examinations using cDNA arrays and real-time quantitative RT-PCR revealed that isoliquiritigenin enhanced the expression of p21(CIP1/WAF1), a universal inhibitor of cyclin-dependent kinases. These results suggest that isoliquiritigenin will be a promising agent for use in chemopreventive or therapeutics against lung cancer.