The ALK tyrosine kinase inhibitor crizotinib has demonstrated clinical efficacy in ALK-rearranged NSCLC patients and is currently under additional phase III clinical development as both initial and second-line therapy for advanced ALK-rearranged NSCLC. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Recent studies have identified and studied two mechanisms of ALK TKI resistance based on evidence from a crizotinib-treated ALK-positive lung cancer patient and in a cell line generated from the resistant tumor. To date four secondary mutations, all identified from crizotinib-treated ALK-rearranged tumor patients, have been reported. These mutations either involve the ‘gatekeeper’ residue (L1196) or sites away from crizotinib binding (F1174L, L1152R and C1156Y). The mechanistic basis for how the different mutations lead to crizotinib resistance is not fully understood. The L1196 mutation may create a steric hindrance for crizotinib binding, whereas the F1174L mutation likely promotes the active conformation of ALK, thus disfavoring crizotinib binding which preferentially binds the inactive conformation of ALK. The other mechanism was activation of EGFR signaling as a bypass signaling mechanisms that contributes to ALK inhibitor resistance. Finally, we discuss the strategies that are underway to clinically overcome acquired drug resistance.