The decision algorithm for treatment of advanced myelodysplastic syndrome (MDS) (intermediate- to very high-risk by the revised International Prognostic Scoring System [IPSS-R]) is complex. Often, the appropriate choice is unknown and not currently addressed by available clinical evidence. Although allogeneic hematopoietic cell transplantation (alloHCT) is curative for some patients with MDS, there is a concurrent high risk of mortality and morbidity. Alternatively, although hypomethylating agents (HMAs) have low toxicity, they are not thought to be curative, with a median increase in overall survival of only 9 months. Initial attempts to improve outcomes with HMAs through addition of novel agents failed, but there is hope that newer combination strategies will improve outcomes. Challenging clinical questions include who should be considered for alloHCT, appropriate timing and preparation for alloHCT, and appropriate therapeutic choices for patients who are not candidates for alloHCT. Given the interplay between alloHCT and non-alloHCT approaches, a unified coordinated approach is optimal for patients with advanced MDS. When possible, patients with advanced MDS should be encouraged to enroll into clinical trials that include alloHCT and non-alloHCT approaches.