With the advent of targeted therapies promising to revolutionise the nature and success of patient care, the field of clinical oncology is facing a highly exciting future. While much of this enthusiasm comes from the hope for improved patient outcomes, a review of clinical response/relapse rates for current therapies provides a more sobering perspective. Given that the majority of patients are intrinsically resistant to the therapeutic potential of these molecules, efforts are now directed at characterising such non-responsive system behaviour and causative molecular insults. Testament to this is an expanding catalogue of target and system-based aberrations, often defined through retrospective analyses of clinical tissue and associated outcome data. What has emerged is a complex picture, where numerous potential sources of cancer-specific aberration can contribute to refractory tumour behaviour. Clinicians, regulators and sponsors must now collaborate to determine how such knowledge should be used to enhance the clinical decision process and associated regulatory guidance.