This study reports a case of HER2-positive, RAS-mutant, microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) exhibiting intrinsic resistance to 5-fluorouracil (5-FU)-based chemotherapy and bevacizumab. Despite multiple lines of prior systemic therapy, the patient achieved significant tumor shrinkage and durable disease control with a combination of PD-1 blockade and a HER2-targeted antibody-drug conjugate (ADC), resulting in a progression-free survival (PFS) exceeding 10 months. Based on this case, we review the current landscape of immunotherapy and ADCs in mCRC, emphasizing the emerging potential of combination strategies for patients harboring rare molecular profiles such as HER2-positive, RAS-mutant MSS tumors. In addition, we discuss the importance of HER2 testing in CRC and the available diagnostic modalities, including immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and liquid biopsy. Given the heterogeneity of HER2 expression in CRC, optimizing testing strategies and treatment selection remains a critical research priority. This review underscores the need for large prospective studies and biomarker-driven trials to refine treatment approaches and improve outcomes in this challenging patient population.AJCR Copyright © 2025.