Recent advances in the molecular biology research of gastrointestinal cancer have led to successful development and approval of targeted therapies such as cetuximab, panitumumab, bevacizumab, aflibercept and regorafenib in advanced colorectal cancer (CRC). These achievements have encouraged the development of innovative targeted therapies that are currently being tested in clinical trials. The increase in median survival of patients with metastatic CRC observed in the last decade is to some extent related to these new drugs. In addition to the inhibitors of epidermal growth factor receptor (EGFR) in RAS wild-type tumors and vascular endothelial growth factor receptor (VEGFR) in unselected populations, there is plethora of different druggable targets being explored in CRC. Two fundamental achievements will impact in the way we develop new targeted therapies in CRC. First, the recently available large scale databases on the genomic landscape in patients with CRC, like the TCGA consortium1, have provided paramount information on the genes that are frequently disregulated in CRC and has provided some fundamental data to differentiate, at least, two different patient populations with CRC: hypermutated and non-hypermutated tumors. The second approach has been built on the possibility of differentiating subtypes of CRC by gene profiling also in large datasets of patients with this disease2,3. Both approaches are at the very beginning steps but have provided some seminal knowledge to establish different molecular subtypes in CRC. In this regard, we have clearly differentiated the BRAF V600E mutant CRC population that, although it accounts only for 5-8% of patients with CRC, has clear dependence/addiction on this mutated gene/protein. Preclinical studies coming from at least two different groups have shown the dependence of these tumors on BRAF but also on some tyrosine kinase receptors that result activated as a compensatory mechanism of secondary resistance4,5. At this time point several trials are evaluating the combination of BRAF or MEK inhibitors with EGFR inhibitors. Preliminary data of these combination studies has yet been presented with encouraging efficacy6. Following the example of the BRAF mutated tumors population, these diagnostic platforms will provide information on some other populations that may be more dependant on selected gene disregulations. Another important concept that has been established is the plasticity CRC has in terms of clonal selection and clonal evolution. It has been shown by different groups that patients with tumors that have wild-type RAS status, once they are treated with EGFR inhibitors -treatment “pressure”-, they start showing an increase in cells that bear RAS mutations7,8. This tumor plasticity concept is fostering the development of new diagnostic approaches that may help us to provide real-time information on the proportion of different clones that compose the burden of the tumor, such as the “liquid biopsy”9. With the availability of new platforms that detect circulating tumor cells (CTCs) or circulating free DNA (cfDNA) we will have the opportunity to determine with non-invasive techniques the variation in the total tumor burden of the disease as well as the characterization of the most frequent clones that compose the tumor at a selected time-point. The clinical application of predictive biomarkers of response to molecular targeted agents has directed the definition of new paradigms in the development of new agents in oncology. The revolution in the knowledge of the biology and the characterization of different molecular subtypes of CRC as well as the availability of new targeted agents will translate in the next future in more therapeutic options in this disease.1Cancer Genome Atlas Network. Nature 2012. 2Tabernero J et al. Proc ASCO GI 2013. 3Dienstmann R et al. Proc ASCO 2014. 4Corcoran RB et al. Cancer Discov 2012. 5Prahallad A et al. Nature 2012. 6Tabernero J et al. Proc ASCO 2014. 7Misale S, et al. Nature 2012. 8Diaz E, et al. Nature 2012. 9Villar E & Tabernero J. Nature 2012