Treatment options are limited for patients with anemia associated with lower-risk myelodysplastic syndromes (LR-MDS). The recent approval of luspatercept for the treatment of anemia associated with very low- to intermediate-risk MDS with ring sideroblasts (RS) or with myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis has provided adult patients and practitioners with a much-needed new therapeutic option. Luspatercept is a first-in-class erythroid maturation agent that exerts its effects on later stages of erythropoiesis. In the phase III MEDALIST trial of patients with LR-MDS with RS, luspatercept (starting dose 1 mg/kg) demonstrated substantial clinical benefit (38% of patients treated with luspatercept vs. 13% of those treated with placebo [p < .001] achieved transfusion independence for ≥ 8 weeks during the first 24 weeks of treatment) and a favorable safety profile. The most common adverse events (AEs), including fatigue, asthenia, dizziness, and diarrhea, were more frequent during the first 4 treatment cycles and subsequently declined. This review provides a comprehensive overview of luspatercept treatment administration, including the mechanism of action, efficacy and safety data, management of dosing, and AEs associated with luspatercept treatment of patients with LR-MDS.