Today, the upfront treatment of metastatic colorectal cancer may span from single-agent fluoropyrimidines to three and even four-drug regimens. While clinical factors, including the crucial item of secondary resectability, certainly contribute to formulate the most appropriate strategy for each patient, also molecular markers are gaining increasing prominence in the decision-making process. The year 2013 is radically changing the way we treat metastatic colorectal cancer. This revolution has started early this year with the presentation of the results from the AVEX and the TRIBE studies at the ASCO Gastrointestinal Cancer Symposium. At the ASCO annual meeting new important results from head-to-head (anti-EGFRs vs bevacizumab) comparative trials were presented as well as new data on RAS activating mutations and resistance to EGFR inhibition. Despite all these novelties, it seems that the best has yet to come. At the time I'm writing ECCO-ESMO congress is approaching and rumors suggest that colorectal cancer oncologists will not be disappointed with some interesting new data coming out.