Background: Cancers of the appendix are rare forms of malignancy that include two major mucin producing tumors, mucinous adenocarcinoma (MA) and goblet cell carcinoid (GCC). There is no clear standard of care for management of these malignancies. We queried whether comprehensive genomic profiling (CGP) of MA and GCC would reveal differences in the pattern of genomic alterations (GA) of these two subtypes of appendiceal cancer and serve as a guide for targeted therapies for this disease. Methods: DNA was extracted from 40 microns of FFPE sections from 20 clinically advanced appendiceal carcinomas (9 GCC and 11 MA). Comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation based libraries to a high mean coverage depth of >600X for 3,230 exons of 182 cancer-related genes, plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of GA including base substitutions, short insertions and deletions, copy number alterations and fusions/rearrangements. Clinically relevant GAs were defined as GAs linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Base substitutions in KRAS were seen in 73% of MA and 11% of GCCs. TP53 mutations were seen in 64% of MA and 22% of GCCs. MYC (36%), SMAD4 (27%), and APC (27%) mutations were found in MA but were absent in GCC. Other GA of low frequency, but clinically relevant in both subsets included ERBB2, GNAS, ARID1A, PIK3CA, NRAS, CTNNB1, BRCA1, BRAF, KDR, PTEN, MCL1, IDH1, FBXW7, and RICTOR. Conclusions: KRAS and TP53 mutations are common in appendiceal MA, but rare in appendiceal GCCs. This confirms the differences in biology and has implications regarding the use of targeted therapies such as anti-EGFR antibody treatments. The high frequency of clinically relevant genomic alterations uncovered in this study that can potentially serve as targets for therapies, either approved or in clinical trials, raises hope that CGP can lead to improvement in outcomes for patients with this aggressive form of malignancy.