Constitutive signaling by the NOTCH1 receptor contributes to more than half of all cases of T cell acute lymphoblastic leukemia (T-ALL). However, blocking the proteolytic activation of NOTCH1 with gamma-secretase inhibitors (GSIs) fails to alter the growth of some T-ALL cell lines carrying the mutated receptor. A recent report by Palomero et al. in Nature Medicine identifies loss of PTEN as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of "oncogene addiction" from the NOTCH1 to the PI3K/AKT pathway. This novel observation suggests the need to simultaneously inhibit both pathways as a means to improve therapeutic efficacy in human T-ALL.