Costs associated with treating cancers such as MDS are increasing as new medicines are developed and combination regimens gain hold. This trend presents an important challenge to MCOs who must respond to changing protocols and rising costs. Whereas the new oncology medications offer a unique opportunity to improve outcomes in patients with MDS, they also demand high financial outlay, which in turn necessitates adjustments in benefits programs. As payers look to manage expenses in ways that satisfy all stakeholders, increasing importance is placed on scientific evidence, survival and QoL benefits, tolerability factors, and evidence-based standards of care. In the treatment of higher-risk MDS, this means weighing those differences between the two hypomethylating agents approved for this indication--azacitidine and decitabine--in terms of proven effectiveness, safe delivery, and survival gains validated in clinical trials as well as potentially reduced costs related to administration method and fewer treatment-related toxicities. The future of MDS treatment in the managed care setting will require complex decision making to determine new treatment guidelines, benefit design, reimbursement plans, ethical considerations, and formulary development. Economic and clinical strategies must aim to make optimal use of novel treatment approaches while meeting the financial objectives of MCOs. The goal is improved patient outcomes at reasonable cost, a challenge that will be addressed only with continued discussion and study. The therapies azacitidine and decitabine may offer a good model for decision making to drive best treatment for MDS while moderating cost.