A vast array of oncogenic variants has been identified for anaplastic lymphoma 
kinase (ALK). Therefore, there is a need to better understand the role of ALK in 
cancer biology in order to optimise treatment strategies. This review summarises 
the latest research on the receptor tyrosine kinase ALK, and how this 
information can guide the management of patients with cancer that is 
ALK-positive. A variety of ALK gene alterations have been described across a 
range of tumour types, including point mutations, deletions and rearrangements. 
A wide variety of ALK fusions, in which the kinase domain of ALK and the 
amino-terminal portion of various protein partners are fused, occur in cancer, 
with echinoderm microtubule-associated protein-like 4 (EML4)-ALK being the most 
prevalent in non-small-cell lung cancer (NSCLC). Different ALK fusion proteins 
can mediate different signalling outputs, depending on properties such as 
subcellular localisation and protein stability. The ALK fusions found in tumours 
lack spatial and temporal regulation, which can also affect dimerisation and 
substrate specificity. Two ALK tyrosine kinase inhibitors (TKIs), crizotinib and 
ceritinib, are currently approved in Europe for use in ALK-positive NSCLC and 
several others are in development. These ALK TKIs bind slightly differently 
within the ATP-binding pocket of the ALK kinase domain and are associated with 
the emergence of different resistance mutation patterns during therapy. This 
emphasises the need to tailor the sequence of ALK TKIs according to the ALK 
signature of each patient. Research into the oncogenic functions of ALK, and 
fast paced development of ALK inhibitors, has substantially improved outcomes 
for patients with ALK-positive NSCLC. Limited data are available surrounding the 
physiological ligand-stimulated activation of ALK signalling and further 
research is needed. Understanding the role of ALK in tumour biology is key to 
further optimising therapeutic strategies for ALK-positive disease.