Chromosomal translocations and single point mutations involving the Anaplastic Lymphoma Kinase (ALK) gene have been described in several human tumors, including anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NCSLC), inflammatory myofibroblastic tumor (IMT) and neuroblastoma. Cancer cells are “addicted” to ALK constitutive activation and are highly sensitive to the treatment with small-molecule inhibitors. Crizotinib, an oral ALK inhibitor, has proved to provide dramatic clinical benefit in patients with NSCLC harboring ALK rearrangements. Nonetheless, acquired drug resistance inevitably develops and leads to tumor progression and relapse. Different mechanisms of crizotinib acquired drug resistance, resembling those reported for other tyrosine kinase targeted therapies, have been recently reported both in cell lines and in patients. Thus, the identification of the molecular mechanisms of crizotinib resistance will be strictly required in order to pursue the appropriate therapeutic options for patients with ALK-rearranged tumors.