Lapatinib, a dual EGFR/HER2 kinase inhibitor, inhibits cell proliferation and survival in part by blocking PI3K/Akt/mTOR signaling. Based on our data, we propose that lapatinib is unable to block proliferation when PI3K/mTOR is not inhibited. Genetic or pharmacologic strategies that improved sensitivity to lapatinib (marked with an asterisk) included expression of dominant negative kinase-dead Akt, knockdown of 4EBP1, and mTOR inhibition by rapamycin or MK-8669. In contrast, knockdown of p70S6K alone did not increase the anti-proliferative activity of lapatinib.