Erika Martinelli, MD, PhD, University of Campania Luigi Vanvitelli, Caserta, Italy, comments on recent updates in research investigating biomarkers of resistance for the treatment of colorectal cancer (CRC). Dr Martinelli discusses the use of liquid biopsies and various mutations which can confer resistance to CRC treatment, such as mutations in KRAS, BRAF, and in the extracellular domain of the vascular endothelial growth factor (VEGF) receptor. Moreover, the ongoing CAVE-2 study (NCT05291156) investigating genes involved in the mechanisms of treatment resistance is discussed. This interview took place at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer (ESMO WCGIC) 2022 in Barcelona, Spain.