Background: Salivary gland cancer (SGC) is a rare cancer and includes twenty-two different entities. In the Radboudumc SGC expertise center, a real-word database was set up to uniformly collect data of SGC subtypes. More than 500 SGC patients have been enrolled and collection of data for 261 patients is currently completed. Here, we describe the retrospective analysis of genetic aberrations found in different SGC entities and the treatment of selected recurrent/metastatic (R/M) patients with genetically matched therapies (GMT). Methods: All SGC patients in the SGC registry of Radboudumc between 2017 and 2022 whose tumors underwent next generation sequencing (NGS) and/or gene fusion analysis within standard of care or clinical trial were included in this analysis. Both primary tumor specimen and metastatic tissue have been used for molecular analyses. GMT was given in basket trials or on basis of compassionate use for clinically relevant genetic aberrations that are considered actionable nowadays. Results: NGS and/or gene fusion analysis data was available for 162 out of 261 patients, and most frequently in salivary duct carcinoma (SDC) patients (82/162). The number of patients with genetic aberrations differed between SGC entities. In 112 patients at least one genetic aberration and/or gene fusion was detected regardless of whether the target was druggable. Ninety-three patients out of 112 patients had R/M disease. Both a gene fusion and one or more mutations were found in six patients (adenoid cystic carcinoma [AdCC], n = 3; SDC, n = 2; and secretary carcinoma [SC], n = 1;). Depending on the SGC subtype, in 14.3 – 100% of the R/M cases with genetic aberrations and/or gene fusions a GMT was started (SDC, 14/60; AdCC, 3/21; SC, 2/2; mucoepidermoid carcinoma, 2/4). The most given GMT among patients were monoclonal antibodies and tyrosine kinase inhibitors (TKI), respectively in nine and eleven patients, moreover immunotherapy was started in one patient. For example, eight SDC patients were treated with ERBB2 targeting agents (4/8 mutations; 4/8 copy number variants in ERBB2), showing a complete response in three patients. Additionally, one partial response and two stable diseases were observed, two patients were lost of follow-up. Two SC patients treated with a TKI based on the presence of the ETV6-NTRK gene fusion showed radiologically a partial response. Conclusions: In 69% of the SGC patients at least one genetic aberration and/or gene fusion was found, and in 23% of the R/M cases GMT was administered. Response differs between entities and GMT; a complete response was achieved after initiation of GMT in several patients. These data justify the use of NGS and gene fusion analysis in all salivary gland cancer entities, notably in subtypes lacking standard systemic therapies as this could offer other therapeutic options.