The transforming growth factor (TGF)-β superfamily comprises more than 30 soluble growth factors that play a central role in erythropoiesis and are part of a tightly regulated myelosuppressive negative feedback loop under physiologic conditions. TGF-β receptor activation and phosphorylation trigger a regulatory circuit of activating and inhibitory SMAD proteins and increased activation of the TGF-β signaling pathway either by a loss of negative feedback or constitutive activation has been associated with the myelosuppression and ineffective erythropoiesis in myelodysplastic syndromes (MDS). Anemia is the predominant cause of morbidity and quality of life impairment in patients with lower-risk (LR)-MDS, and there are very limited therapy options for these patients after failure of erythropoiesis stimulating agents (ESAs). Targeting the aberrant TGF-ß signaling pathway has therefore been investigated as a promising therapeutic approach to resolve the ineffective erythropoiesis in LR-MDS. In this article, we provide a brief overview of the TGF-β signaling cascade in hematopoiesis under physiologic conditions and its role in MDS pathogenesis. We also review preclinical and clinical data for the activin receptor type IIA ligand traps sotatercept and luspatercept that have recently shown promising results in overcoming the myelosuppressive effects of TGF-β signaling alterations to improve hematopoiesis in transfusion-dependent, non-del(5q) LR-MDS patients. Additional potential targets within the TGF-β pathway have also been identified in preclinical experiments and may provide further therapeutic options. Finally, combining different TGF-β pathway inhibitors or using them in combination with ESAs or the immunomodulator lenalidomide might have synergistic effects as well.