Background: Appendiceal cancers are rare and there are no established guidelines for adjuvant treatment and metastatic disease. Methods: Samples were identified from > 60,000 global tumors analyzed at a referral molecular profiling CLIA certified laboratory (Caris Life Sciences) for biomarkers of drug sensitivity, under an approved protocol. 285 samples with primary tumor sites of appendix were identified (M/F ratio of 38%/62%; mean age of 55). Approximately 80% of samples were adenocarcinomas, 10% carcinoids, and 10% of indeterminate histology. IHC assays (n=273) were performed with up to 30 biomarkers; FISH (n=39) for c-Myc, cMET, EGFR, HER2 and/or TOPO2A gene copy amplifications; and sequencing done ( n= 223) for KRAS, EGFR, PIK3CA, and BRAF. Results: Targets on IHC: 97% high BCRP; 16% high KIT; 80% high COX-2; 50%high EGFR; 30% low MGMT, 81% high MRP1, 35% high PDGFR, 82% low PTEN, 27% high RRM1, 39% high SPARC; 67% high TLE3, 27% high TOPO2A ; 63% high TOPOI, and 99% negative TS. Targets on FISH: 5% amplified EGFR and 0% amplified Her2/Neu. Sequencing results: 53% mutated KRAS and 2% mutated BRAF. Conclusions: The high levels of drug resistance proteins (BCRP and MRP1) highlights the difficulty in treating these tumors. The incidence of KRAS mutations (53%) and low expression of TS (99%) is noteworthy, and points towards using 5FU/capecitabine as a backbone of therapy. Therapeutic options are varied and options include TOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), MGMT (temazolamide), BRAF inhibitors (vemurafenib, dabrafenib) 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, and to pursue whole genomic sequencing. Supported by a grant from Caris Life Sciences.