Despite the availabilty of active chemotherapy combinations and novel targeted agents, the prognosis in advanced non-small cell cancer (NSCLC) remains poor. Similarly, although the efficacy of adjuvant chemotherpy has recently been established, the risk of disease recurrence after surgery for early stage disease remains high. Some patients enjoy sustained benefit from currently available drugs, but overall results in unselected patient groups are modest. This marked inter-patient variation reflects the molecular heterogeneity of NSCLC, a heterogeneity which is increasingly understood to arise at the level of the cancer genome. The wide range of somatic genetic and epigenetic events that drive the lung cancer phenotype is now beginning to inform the selection of patients for treatment with both cytotoxic and targeted therapies. Furthermore, it is becoming apparent that germline genomic variability may also need to be taken into account in making treatment decisions for NSCLC patients.