In order to elucidate the role of MBD4 in colorectal tumorigenesis, we conducted a combined human-mouse study: we assessed the frequency, pattern and significance of germline and somatic MBD4 mutations in a series of human CRC patients and tumors, respectively, and tested whether biallelic inactivation of Mbd4 in a murine model may affect tumorigenesis and/or modify the tumor-predisposing phenotype on a cancer susceptible Mlh1−/− background. This evidence concerns the gene MLH1 and neoplasm.