Lung cancer is the most common cause of cancer- related death worldwide, causing over 1.2 million deaths each year. Non-small-cell lung cancer (NSCLC) consists of a group of malignancies that are pathologically and molecularly diverse but that are all characterised by a poor prognosis. Survival rates for lung cancer patients have improved very slowly and only to a modest degree owing partly to poor funding for research into this malignancy and stigma associated with smoking, as well as relative chemo-resistance. However, in recent years, NSCLC has become an exemplar for precision medicine, mainly following development of drugs targeting the receptors of epidermal growth factor and anaplastic lymphoma kinase. While epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors are only applicable to a minority of patients and benefits are almost invariably short-lived, current studies indicate that at least 50% of patients with NSCLC have a targetable mutation. With a growing armamentarium of inhibitors against these targets in development, there is a hope that a greater proportion of patients will benefit from precision medicine and that such benefits will be sustained. However, there remain significant challenges in the development of precision medicine in NSCLC. These include: identification and validation of new targets; ensuring biopsies are fit for purpose; tumour heterogeneity; requirements for serial tumour assessments; and not least cost. In this review, we will discuss the current status of precision medicine in NSCLC as well as how basic and translational research are paving the way towards overcoming the above challenges. In addition, we will pay attention to clinical strategies in respect to liquid biopsies and the potential use of extracellular vesicles such as exosomes in cancer therapeutics.