Appreciation of heterogeneity of the molecular phenotype of cancers at both the interpatient and the intrapatient level has begun to impact on systemic treatments for metastatic disease in the clinic. In non-small cell lung cancer, for example, putative molecular drivers can be identified in over half of patients with adenocarcinoma the most common histological subtype of NSCLC. Phase III studies have demonstrated the superiority of EGFR inhibitors and ALK inhibitors over conventional chemotherapy in patients whose tumours harbour EGFR mutations or ALK gene rearrangements respectively. Responses to gentotype directed therapy have also been reported in patients with molecular alterations including ROS1, cMET, BRAF, and Her2. However despite dramatic initial responses to therapy patients treated with these agents invariably develop disease progression. However, with increasing understanding of the molecular mechanisms for acquired resistance has come opportunity to use novel agents that target clones responsible for resistance. In addition, recognition of clonal heterogeneity in response to targeted agents, provides a rationale for aggressive local therapy for “oligoprogressing” disease with modalities including surgery and sterotactic radiotherapy.