Translational research is about transforming progress in basic research into products that benefit patients. Here I discuss some of the key obstacles to effective translational research in oncology that have previously received limited attention. Basic research often does not go far enough for straightforward clinical translation, and long-term, high-risk endeavours to fill these key gaps have not been adequately addressed either by industry or by the culture of investigator-initiated research. These key gaps include the identification of causative oncogenic mutations and new approaches to regulating currently undruggable targets such as tumour suppressor genes. Even where an inhibitor of a key target has been identified, new approaches to clinical development are needed. The current approach of treating broad populations of patients based primarily on primary cancer site is not well suited to the development of molecularly targeted drugs. Although developing drugs with predictive diagnostics makes drug development more complex, it can improve the success rate of development, as well as provide benefit to patients and the economics of healthcare. I review here some prospective Phase III designs that have been developed for transition from the era of correlative science to one of reliable predictive and personalised oncology.