The prognosis in advanced non-small cell cancer (NSCLC) remains poor despite the introduction of several new cytotoxic drugs in the past decade. New approaches are required, and an improved understanding of lung cancer biology is identifying molecular mechanisms that are potential targets for novel therapies. Antagonists of signalling via the erbB and VEGFR families of transmembrane receptors have promising activity in NSCLC, and survival benefit has already been demonstrated for both erlotinib and bevacizumab. Although some patients enjoy dramatic and sustained responses to some of the new targeted drugs, overall response rates in unselected NSCLC patient groups are modest. This reflects the molecular heterogeneity of the disease; further clinical progress will require improved patient selection for treatment with both novel agents and established chemotherapy drugs. Here, we review recent advances in NSCLC biology likely to provide insight into such selection strategies.