In this study, using an in vitro human tumor model, we show that non-small lung adenocarcinoma A549 cells after treatment with DNA damaging antitumor drugs become permanently growth-arrested as a result of so-called drug-induced premature senescence (pseudo-senescence). However, a small fraction of drug-treated cells escapes pseudo-senescence that leads to re-growth of tumor cell population after drug treatment. We show that this re-growth is associated with the presence of cancer stem cells (CSCs) in lung tumor cell population. We also document that re-growth of CSCs can be greatly delayed if lung tumor cells are treated with drug/caffeine combination that leads to the inhibition of the ATM/ATR pathway and decreased phosphorylation of PKB/Akt at Ser473. We show that in non-treated A549 cells caffeine by itself induces a reversible growth arrest that is associated with increased fraction of so-called side population cells, containing CSCs. These results point to the existence of an unknown, caffeine-sensitive mechanism that controls the number of CSCs in lung tumor cell population. Full characterization of this mechanism may lead to the development of innovative cancer therapies, which are based on small molecular weight inhibitors of CSC differentiation and self-renewal, which mimic caffeine action. Our results have also important implications for drug screening tumor models in vitro.