Defining key driver mutations in cancer, the resulting aberrations in molecular mechanisms and the subsequent phenotype underpins the development and implementation of novel personalized medicine strategies. The literature is replete with biomarkers of prognosis and therapeutic responsiveness identified in single cohorts of patients that have not been independently validated and as a consequence, not developed. Integrating companion biomarker discovery with therapeutic development at the preclinical stage creates the opportunity to identify candidate biomarkers early, which would significantly facilitate both biomarker and therapeutic development. Advances in "-omic" technologies have led to large-scale efforts in characterizing and cataloguing the full range of aberrations in cancer. These include the International Cancer Genome Consortium and The Cancer Genome Atlas, which aim to comprehensively catalogue the range of genomic aberrations for large numbers of cancers for a progressively increasing range of cancer types and subtypes. The technical challenges associated with achieving these goals in some instances have required the generation of primary xenografts and cell lines. These extensively characterized model systems will provide an unprecedented resource for the discovery of biomarkers of therapeutic responsiveness for established therapies, and the development of companion biomarkers linked with preclinical novel therapeutic development in the future.