The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in 
the development of the brain and can be oncogenically altered in several 
malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large 
cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal 
rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other 
tumors, ALK copy-number gains and activating ALK mutations have been described. 
Dramatic and often prolonged responses are seen in patients with ALK alterations 
when treated with ALK inhibitors. Three of these-crizotinib, ceritinib, and 
alectinib-are now FDA approved for the treatment of metastatic NSCLC positive 
for ALK fusions. However, the emergence of resistance is universal. Newer ALK 
inhibitors and other targeting strategies are being developed to counteract the 
newly emergent mechanism(s) of ALK inhibitor resistance. This review outlines 
the recent developments in our understanding and treatment of tumors with ALK 
alterations.