Mutations in the RAS/RAF/MEK/ERK pathway leading to constitutive activation and uncontrolled cellular growth have been identified in various human malignancies, making this pathway a target for potential therapeutics. The activating mutation is one well-characterized oncogenic mutation that has been described and targeted with clinical success in various malignancies, including melanoma and hairy cell leukemia. Although -directed treatments have yielded clinical benefit in a subset of tumor types, such as melanoma, thyroid cancer, and lung cancer, BRAF inhibition fails to confer a clinical benefit in colon cancer. Identification of patients for whom BRAF inhibition may produce clinically meaningful outcomes is imperative. The incidence of mutations in neuroendocrine carcinoma (NEC) is estimated to be 5% to 10%. A recent case series demonstrated benefit in targeting the mutation in metastatic high-grade rectal NECs. Combination BRAF and MEK inhibition is known to yield improved outcomes compared with BRAF inhibition alone in melanoma. This report presents 2 patients with high-grade colorectal NECs who had different responses to treatment with combined BRAF/MEK inhibition after experiencing disease progression through first-line platinum-based chemotherapy. One patient experienced an excellent initial response to therapy before ultimately experiencing progression, and in the other patient initially had stable disease before eventually experiencing progression. These cases highlight the complicated role mutations play in gastrointestinal NECs, and the need for further research to identify not only patients who may benefit from -directed therapies but also strategies to avoid development of resistance.