Targeted therapies in colorectal cancer (CRC) are currently mostly limited to the unresectable or metastatic setting [1,2,3,4,5,6]. The incorporation of molecular profiling technologies to the clinic in synergy with the broadening of targeted agents and druggable genomic aberration landscape has increased traction lately towards incorporating molecularly targeted therapies as single-agents or in combination to well-established chemotherapy schemes . Alterations involving “rearranged during transfection” (RET) kinases are such potential targets. RET is a proto-oncogene whose loss of function mutations are associated with the development of Hirschsprung's disease and gain of function mutations are associated with the development of various types of human cancer, however, they are rare in CRC . We present a case of a patient with CRC with RET fusion treated with a LOXO-292, a selective RET-inhibitor leading to an exceptional response, highlighting the impact of next-generation genome sequencing on the clinical management of CRC patients and reinforcing the notion that RET alterations are actionable therapeutic targets when present despite the tumor type. Although the incidence of RET fusions in CRC is low, prospective use of next-generation genome profiling should be encouraged to identify patients who may potentially benefit from selective RET inhibition.