The hypomethylating agents (HMAs), decitabine and azacitidine, are valuable treatment options in acute myeloid leukemia patients who are not eligible for intensive chemotherapy. Both agents are generally well tolerated, and complications most commonly relate to myelosuppression. Antibiotic / antifungal use, regular monitoring, and proactive patient education are important to minimize these events, and reduce the need for dose delay. Responses to HMAs are often not evident for up to 6 cycles, and there is currently no validated clinical marker for predicting response. Hence, treatment should be continued for at least 4–6 cycles to ensure that patients have sufficient opportunity to respond. Delivery of insufficient numbers of cycles is a key reason for HMA failure, and premature discontinuation must be avoided. Genetic factors offer potential for better predicting responders to HMAs in future, but require further study.