Deciding on whether or not to treat stage II colorectal cancer (CRC) patients with adjuvant chemotherapy is one the most challenging questions for clinical oncologists. Prospective clinical trials and pooled analyses suggest that the survival benefit associated with postoperative chemotherapy is rather small. Clinical guidelines laid out by the American Society of Clinical Oncology and other similar organizations recommend the clinicians to consider clinicopathological features that are associated with poor prognosis when deciding whether or not to use adjuvant treatment. However, this decision is rather complex and not straightforward, requiring the integration of factual information, acceptance of uncertain outcomes, and a value judgment from the patient. Recently, there has been an attempt to identify novel panels of composed molecular and biochemical markers that could be used to more precisely define prognosis and predict the benefit of adjuvant treatment in CRC patients. However, none of these gene signatures has shown to possess sufficient reproducibility across different studies, thus greatly reducing their clinical utility. We have recently identified Myosin Vb (MYO5B), in combination with its adapter protein RAB8A, to be a promising prognostic biomarker in stage II CRC patients. The MyoRPROG assay will be used for the determination of each patient’s individual risk for relapse and, most importantly, allow for the segregation of patients that will benefit from chemotherapy, from patients that do not require these treatments and can instead be treated with other less arduous and costly methods. The MyoRPROG test will support physicians with their complex treatment decisions.During the “proof of concept” study, we would like to pave the way to the clinics by carrying out both the clinical and analytical validation of our biomarker as well as to develop a prototype kit for preliminary clinical use.