Human epidermal growth factor receptor 2 (HER2) aberrations are found in several high-grade salivary gland carcinomas (SGCs) with variable rates according to the pathologic subtype. HER2 alterations are constantly absent in low-grade and indolent SGCs. High-grade tumors, especially salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified (NOS) are characterized by higher frequencies of HER-2 gene alterations (32% SDC, 15–17% adenocarcinoma NOS, carcinoma ex pleomorphic adenoma 32%). Independent of the underlying biological mechanism leading to HER2 amplification, HER2-positive (HER2+) SDC patients have a worse prognosis than their HER2-negative counterparts, especially in the recurrent/metastatic (R/M) setting. Therefore, HER2-overexpressing and amplified SDCs are different entities compared to HER2-negative ones. Mimicking the classification of breast cancers (hormone+, HER2−; hormone+, HER2+; hormone−, HER2−; triple-negative disease, meaning hormone- and HER2−), a similar grouping was proposed for SDC: apocrine A and B (androgen receptor positive [AR+], HER2−, with low and high ki67, respectively), apocrine HER2 (AR+, HER2+), HER2-enriched (AR−, HER2+), double negative (AR−, HER2−). However, AR overexpression is almost definitional in SDCs. From a therapeutic point of view, intense staining and an expression ≥70% are the conditions to predict the clinical benefit of an antiandrogen treatment. On the contrary, AR-negative SDCs are very rare, and this diagnosis should be regarded with skepticism, so a second look at the diagnosis by an expert pathologist should be considered. Treatment of recurrent/metastatic (R/M) SDC patients may be based on the possible AR and HER2 expression combinations. Patients with AR+ HER2+ SDC should be offered androgen deprivation treatment (ADT) and/or chemotherapy (CT) and/or anti-HER2 therapy; patients with AR+ HER2-negative disease may benefit from ADT and/or CT, while patients with HER2-enriched disease should receive anti-HER2 +/− CT. In case of double negative SDCs or following disease progression on systemic treatments (ADT, anti-HER2, CT, or their combinations), if patients are not eligible for clinical trials, a molecular characterization (e.g., through next-generation sequencing) should be performed to assess any actionable genomic alterations.