ALK rearrangements occur in 4% of non small cell lung cancer patients, which is approximately 8,000 cases in the US and 40,000 cases worldwide each year. Although most ALK-positive individuals initially respond to ALK tyrosine kinase inhibitors (TKIs), the majority develop drug resistance and relapse within 1 year. Jeff Engelman and colleagues now report secondary mutations in ALK in individuals with acquired resistance to the ALK TKI crizotinib (Xalkori, Pfizer) (Sci. Transl. Med., published online 25 January 2012; doi:10.1126/scitranslmed.3003316). The authors analyzed tumors from 18 crizotinib-resistant individuals and found that 4 harbored mutations in ALK, including 3 missense variants and 1 insertion, with all the mutations affecting amino acids near the ATP-binding domain of ALK. By examining tumor specimens taken before crizotinib administration, the authors confirmed that the ALK mutations were not present before treatment. Each of the ALK variants was expressed in Ba/F3 cells that express EML4-ALK, and their effects on cell survival after crizotinib treatment were tested. All four mutations were found to confer resistance to crizotinib, although to varying degrees. The authors also tested the effect of three next-generation ALK inhibitors and found that each had different levels of activity against particular mutations. The study suggests that personalized combinatorial therapies in crizotinib-resistant patients are warranted.