Background: Undifferentiated carcinoma with osteoclast-like giant cells/osteoclast-like giant cell reaction (UC-OGC) is a rare form of pancreatic cancer historically associated with a poor prognosis. Molecular tumor profiling provides new information about tumor origins and a more nuanced understanding of the potential efficacy of different chemotherapeutic agents. Presentation: A 69-year-old man presented with a 13-cm periampullary pancreatic mass. Biopsy of a neighboring lymph node was consistent with adenocarcinoma. After neoadjuvant chemoradiation, the patient underwent resection and the tumor was consistent with UC-OGC. Next-generation sequencing was performed with genomic and proteomic analyses analyzed by a molecular tumor board review. These analyses revealed genetic alterations similar to those seen in pancreatic ductal adenocarcinoma, as well as potential therapeutic targets for the patient's subsequent therapy. Conclusions: Understanding a tumor's genetic changes allows for better understanding of its biology and may improve treatment efficacy. We believe that future study in tumor profiling will improve our understanding of rare cancers such as UC-OGC and also pave the way for the use of novel therapies to specifically target mutations in a broad range of more common tumors.