Lung cancer continues to be a major cause of cancer related morbidity and mortality globally. Enhanced biomolecular characterisation of non small cell lung cancer (NSCLC) has revealed that at the cellular core, lung cancers are genetically unique, each cancer distinguished by driver mutations that trigger cellular pathways that initiate and propel tumour cell growth, affect the propensity for metastasis and are likely to play a critical role in the development of selected resistance mechanisms, especially under the pressure of targeted therapy. Most patients present at a surgically unresectable stage. The increasing number of approved drugs that target underlying driver mutations along with the utilisation of next generation sequencing (NGS) technologies provide the best solutions to extract the most diagnostically useful information from the small samples available from biopsies and cell blocks. The detection of rare mutations may not be possible using a serial testing approach as tissue is quickly depleted after performing 3- 4 tests. Targetable driver mutations which may be found more than 60% of NSCLC cases coupled with driver mutation-based targeted therapies, generally enhance the therapeutic response and quality of life for these select group of patients. Indeed, NGS may be the only cost effective and accurate method to detect some molecular events such as Met exon 14 skipping, NTRK fusions and Exon20 insertions, all of which are eminently targetable. Furthermore, NGS testing of liquid biopsies is gaining traction and as the sensitivity levels improve, is likely to become standard of care in the management of NSCLC patients in the foreseeable future.