Anaplastic lymphoma kinase (ALK) rearrangement is detected in 3-7% of patients 
with non-small-cell lung cancer. Crizotinib is an ALK inhibitor, which was 
approved in 2011 for the treatment of ALK-positive lung cancer. Despite the 
initial enthusiasm, most of the patients develop resistance within the first 
year of treatment. The main mechanisms are secondary mutations and bypass track 
activation. Moreover, crizotinib has low penetration into the central nervous 
system. The need to overcome these limitations has led to the development of 
second-generation inhibitors that have better effectiveness against 
crizotinib-resistant mutations and brain metastases. Ceritinib and alectinib are 
the only approved drugs of this group. Many ongoing trials try to define the 
most appropriate agent for the treatment of ALK-positive lung cancer depending 
on the responsible mechanism. This review focuses on the current data regarding 
the potential mechanisms of resistance to ALK inhibitors and the strategies to 
overcome it.