In the last 20 years, improvements in metastatic colorectal cancer treatment lead to a radical raise of outcomes with median survival reaching now more than 30 months. Despite that, the identification of predictive and/or prognostic biomarker still represents a challenging issue, and until today, although clinician and researchers might face with a deeper knowledge of biological mechanisms related to colorectal cancer, many pieces of evidence underline the heterogeneity and the dynamism of such disease. In the present review, we describe the road leading to the discovery of RAS mutations, BRAF V600E mutation, and microsatellite instability role in colorectal cancer; second, we discuss some of the possible major pitfalls of biomarker research, and lastly, we give new suggestions for future research in this field.