The efficacy of targeted therapies in patient populations selected for treatment on the basis of the molecular features of their tumours is shifting the current focus of treatment to biomarker-driven clinical trials. Phase I trials provide an arena for early hypothesis testing, examining not only safety and toxicity, but also target engagement, biologically effective dosages, and the appropriate patient population. In this Perspectives article, we describe this new trend in early drug development, establishing the different approaches for building a pre-screening programme in an academic institution that is involved in early drug development. Our experience establishing the phase I programme at Vall d'Hebrón serves as an example of how these approaches can be integrated in ongoing trials, and we believe these considerations will help others to implement similar programmes in their institutions.