Genomic technologies have revolutionized the way we study and understand cancer. The advent of next-generation sequencing technology in particular is now starting to change the clinical management of non-small-cell lung cancer. These technologies have helped us to refine prognostication and identify new driver mutations that can allow subselection of patients for therapeutic intervention. However, several limitations and challenges must be overcome before these technologies are widely accepted in diagnostic laboratories. It will be important for clinicians and diagnostic laboratories to consider sample type, analytical platform, cost, data security and ethics, and the bioinformatics challenges associated with ‘big data’, before widespread integration to the clinic. If these challenges can be overcome, then genomics has the potential to change clinical management of lung cancer.