SBA is a rare malignancy, which, owing to its anatomic proximity to the large bowel, has historically been perceived to have a clinical behavior similar to CRC. However, aside its lower incidence and worse prognosis, comprehensive molecular profiling data speak in favor of its uniqueness. Owing to non-specific symptoms and the lack of screening programs, even in high-risk individuals, this disease is often diagnosed at an advanced stage. In patients with localized disease, surgical resection with adequate lymph node sampling represents the only treatment with a chance of cure. However, up to a third of patients with resectable disease experiences a relapse. Therefore, in particular for patients at higher risk of relapse, adjuvant chemotherapy with a fluoropyrimidine-based regimen is recommended, although definitive data on its efficacy are lacking. Enrollment in the BALLAD trial (NCT02502370), which will hopefully clarify the role of adjuvant chemotherapy in resected SBA, is strongly encouraged. Patients with stage IV disease are usually treated with systemic chemotherapy, which includes oxaliplatin-based doublets in the first-line setting and taxanes or irinotecan-based regimens in the second-line setting. Of note, a phase II, open-label, randomized trial is actually ongoing with the aim to compare the FOLFIRI regimen with paclitaxel plus ramucirumab in patients with pre-treated locally advanced or metastatic SBA (NCT04205968). Data about surgical resection of metastatic disease are extremely limited, and cases with potentially resectable oligometastatic disease should be discussed within experienced multidisciplinary teams. Recent in-depth genomic characterization of a large series of SBAs demonstrated its unique molecular profile as compared to neighboring GC and CRC [16]. Of note, potential targetable genomic alterations were identified in 91% of cases (including HER-2 amplifications/mutations, EGFR amplifications/mutations, MEK1 and BRAF mutations, and PI3K pathway activating alterations), thus suggesting further therapeutic options in an orphan disease of approved targeted agents. As genomic profiling techniques become more available in the near future, enrollment in clinical studies with innovative designs, especially basket trials, aiming at assessing the outcome of matched target therapies will be of paramount importance. On the other hand, developing new preclinical models to test potential therapeutic strategies will be equally crucial. Despite the great expectations after the introduction of immune checkpoint inhibitors (ICIs) in the therapeutic armamentarium of various neoplasms, aside for MSI-H tumors, clinical trial results in the specific setting of SBA have been quite disappointing. However, in the work by Schrock and colleagues [16], a substantial proportion of MSS SBAs had a high TMB, a potential biomarkers of ICIs efficacy. Overall, the fraction of TMB-high SBAs was 9.5%, significantly higher than that of GC or CRC, thus suggesting further investigations on the role of ICIs in SBA. Figure 2 provides an algorithm for the management of patients with a clinical suspicion of SBA.