The authors sought to evaluate whether sisomicin has a place in the current therapeutic armamentarium. PubMed and Scopus databases were systematically searched. Ten cohort studies and 11 case reports and case series were included evaluating, in total, 383 Gram-positive and 83 Gram-negative isolates. Sisomicin was active in vitro against 41% of Enterococcus spp., 97% of Staphylococcus spp. and was the most active in vitro (74%) aminoglycoside against Stenotrophomonas maltophilia isolates in one study. Regarding clinical effectiveness, sisomicin topical cream was effective in all 290 patients with pyoderma in one study, while the intravenous formulation of sisomicin was effective as prophylaxis for the development of postoperative pneumonia in 91% of lung surgery patients in another. In conclusion, sisomicin may be useful against certain pathogens; however, clinical data are scarce. Further studies are needed and may shed additional light in this area.