Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature and drug responsiveness. Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups has been limited. KRAS and BRAF mutations are prevalent genetic alterations in CRCs, and patients with mutations in either of these genes have a worse prognosis and are resistant to anti-EGFR treatments. In this study, we have found that a subgroup of CRCs, defined by having either KRAS or BRAF (KRAS/BRAF) mutations and BCL2L1 amplification, can be effectively targeted by simultaneous inhibition of BCL2L1 (with ABT-263) and MCL1 (with YM-155). This combination treatment of ABT-263 and YM-155 was shown to have a synergistic effect in vitro as well as in in vivo patient-derived xenograft models. Our data suggest that combined inhibition of BCL2L1 and MCL1 provides a promising treatment strategy for this genomically defined CRC subgroup.