Background: The current mainstay of clinical molecular testing for advanced colorectal carcinoma (CRC) is mutation analysis for KRAS, NRAS, and BRAF to determine anti-EGFR therapy eligibility. However, the growing number and potential of targeted therapies has led to the need for broader molecular panels to triage patients. Here, we report our experience with a next-generation sequencing (NGS) assay that enables the detection as well as molecular characterization of CRC with rare and potentially targetable receptor tyrosine kinase (RTK) alterations. Methods: We use a hybrid capture-based NGS assay encompassing all exons of 341 cancer genes (MSK-IMPACT) to sequence tumor against matched normal to detect potentially actionable somatic alterations including point and indel mutations, copy number alterations, and selected structural rearrangements. CRC with hotspot mutations in KRAS/ NRAS exons 2-4 and BRAF exons 11 and 15 were excluded from further analysis as these downstream mutations often lead to primary resistance. Results: Seventy four of 164 CRC had wild type RAS/RAF. Twelve cases (16%) of this subgroup harbored RTK alterations previously reported to be activating and potentially targetable. Hotspot mutations commonly seen in other tumor types were also identified, including one each of EGFR p. L858R in a patient also harboring an ERBB2 p. S310F, EGFR p. L861R, and ERBB2 p. V842I a patient with ERBB2 amplification. One each of in-frame fusions of RTKs were also detected: ERBB2-GRB7 in a patient with ERBB2 amplification, RET-NCOA4, and ETV6-NTRK3. Additional RTK amplifications were also observed in the absence of other oncogene alterations, including FGFR1 (n = 3), ERBB2 (n = 2), MET (n = 1) . No ALK or ROS1fusions were detected in any of the 164 CRC. Of these 12 patients with potentially targetable RTK alterations, 3 have already enrolled in ‘matched’ targeted therapies. Conclusions: Using a broad molecular assay to interrogate potentially actionable mutations, approximately 16% of RAS/ RAF wild type CRC harbor RTK alterations that are known to be activating and potentially responsive to inhibition.