Despite rapid progress in annotating the human genome, progress in biomarker discovery has been limited, in part, due to the restricted adoption of biomarker analysis in clinical trials. In this short review we present a roadmap to drive progress in the field of personalized cancer management and patient stratification. We suggest that improved understanding of disease biology and drug response in advance of clinical trial design would enable novel biomarkers to be identified and prospectively evaluated during early phase trials; there will also be value in banked material from completed clinical trials to identify and validate biomarkers. Such progress requires standardized tissue collection protocols, novel bioinformatics strategies integrated with functional genomics analysis, and next generation sequencing technologies. We argue that the failure to adopt these methods rapidly into clinical trial design will increase late stage drug attrition, waste trial resources, and risk patient harm within unselected cohorts.