We sought to identify genomic alterations (GA) in salivary gland adenocarcinomas, not otherwise specified (NOS), salivary duct carcinomas (SDC), carcinoma ex pleomorphic adenoma (ca ex PA), and salivary carcinoma, NOS. DNA was extracted from 149 tumors. Comprehensive genomic profiling (CGP) was performed on hybridization-captured adaptor ligation-based libraries of 182 or 315 cancer-related genes plus introns from 14 or 28 genes frequently rearranged for cancer and evaluated for all classes of GAs. A total of 590 GAs were found in 157 unique genes (mean 3.9/tumor). GAs in the PI3K/AKT/mTOR pathway were more common in SDC (53.6%) than other histologies (P = 0.019) Cyclin-dependent kinase GAs varied among all histotypes: adenocarcinoma, NOS (34.6%); SDC (12.2%); ca ex PA (16.7%); carcinoma, NOS (31.2%; P = 0.043). RAS GAs were observed: adenocarcinoma, NOS (17.3%); SDC (26.8%); ca ex PA (4.2%); and carcinoma, NOS (9.4%; P = 0.054). ERBB2 GAs, including amplifications and mutations, were common: adenocarcinoma, NOS (13.5%); SDC (26.8%); ca ex PA (29.2%); carcinoma, NOS (18.8; P = 0.249). Other notable GAs include TP53 in >45% of each histotype; NOTCH1: adenocarcinoma, NOS (7.7%), ca ex PA (8.3%), carcinoma, NOS (21.6%); NF1: adenocarcinoma, NOS (9.6%), SDC (17.1%), carcinoma, NOS (18.8%). RET fusions were identified in one adenocarcinoma, NOS (CCDC6-RET) and two SDCs (NCOA4-RET). Clinical responses were observed in patients treated with anti-HER2 and anti-RET-targeted therapies. CGP of salivary adenocarcinoma, NOS, SDCs, ca ex PA, and carcinoma, NOS revealed diverse GAs that may lead to novel treatment options. Clin Cancer Res; 22(24); 6061-8. ©2016 AACR.