FOXO transcription factors are important regulators of cell fate decisions, capable of inducing cell death as well as promoting cell survival and resistance to environmental stress. As is the case for many cancers, apoptosis of leukaemic cells in response to chemotherapeutic drugs such as doxorubicin is dependent upon FOXO activation. Surprisingly, prolonged FOXO activity paradoxically promotes drug-resistance in leukaemia by enhancing the expression of critical signal intermediates that drive the activity of the Class 1A PI3-K/Akt survival pathway. Additionally, under continuous stress, FOXO factors also induce the expression of genes important for drug efflux, antioxidant defence, and DNA damage repair. Thus, the same effector molecules, FOXOs, are responsible for not only the initial therapeutic response to cancer drugs but also the subsequent acquisition of resistance. This emerging evidence demonstrates that FOXO factors have a dual role in stress response and function at the axis of cancer drug sensitivity and resistance. Nevertheless, the mechanism that allows FOXO to escape the negative control of the PI3-K/Akt pathway in response to persistent cytotoxic stress and to switch its control from pro-apoptotic to pro-survival target genes is not well understood but likely to involve a series of defined post-translational protein modifications.