Azacitidine is now considered one of the standard-of-care agents for patients with high-risk myelodysplastic syndromes who are not candidates for high-dose chemotherapy. Considering the mechanism of action of the agent, it is critical to maintain adequate dose intensities for prolonged periods of time in order for treatment to be effective. Therefore, aggressive prevention as well as treatment of side effects is critical. The drug mainly causes hematological toxicity that is managed with growth factor support, blood transfusions, and dose and schedule adjustment. Nonhematological side effects are mainly gastrointestinal and cutaneous in nature, and can be easily managed with symptomatic treatment and correct administration techniques.