Hypomethylating agents (HMAs) have changed the landscape of the management of patients with higher-risk myelodysplastic syndromes (HR-MDS). HMAs have improved hematopoiesis and quality of life and, in the case of azacitidine, prolonged survival in a large randomized trial. However, multiple real-life and registry analyses have demonstrated minimal survival gains at the population level after the approval of HMAs. Furthermore, the 24-month median survival observed with azacitidine in the landmark AZA-001 trial has not been replicated in population-based studies or in other clinical trials using azacitidine monotherapy arms. Herein, we critically review the accumulating data suggesting that the actual survival impact of HMAs, especially azacitidine, in patients with HR-MDS is significantly lower than what was observed in the AZA-001 trial and what often is quoted to patients, and discuss the potential explanations for this discrepancy. We also present the rationale for why front-line clinical trial enrollment should be always considered and discussed with every newly diagnosed patient with HR-MDS rather than defaulting to the routine use of HMAs. Finally, we review the challenges to wider-scale enrollment in front-line HR-MDS clinical trials and suggest solutions to accelerate this process with the ultimate goal of achieving a real and substantial change in the natural history of this aggressive malignancy.