Background: Appendiceal cancers are rare and consist of carcinoid, mucocele, pseudomyxoma peritonei, goblet cell carcinoma, lymphoma, and adenocarcinoma histologies. Current treatment involves surgical resection or debulking, but no standard exists for adjuvant chemotherapy or treatment for metastatic disease. Methods: Samples were identified from 60,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory. 460 samples with appendix primary tumor sites were identified (male/female ratio of 2:3; mean age = 55). 62% of samples were adenocarcinomas (used for analysis); the rest consisted of 9% goblet cell, 15% mucinous; 6% pseudomyxoma, and less than 5% carcinoids and 2% neuroendocrine. Tests included sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and gene amplification (FISH or CISH). Results: % positive of total adenocarcinoma cohort are shown (see Table). Conclusions: Appendiceal adenocarcinomas show high levels of drug resistance proteins (BCRP and MRP1), which highlight the difficulty in treating these tumors and suggest an individualized approach to treatment. Therapeutic options include TOPO1 inhibitors (irinotecan/topotecan), PDGFR antagonists (regorafenib, axitinib), MGMT (temozolamide), and SPARC (nab-paclitaxel). These findings indicate the need to evaluate patient samples for patterns in marker expression and alteration, in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers (supported by a grant from Caris Life Sciences).