Patients with hematologic malignancies are at increased risk of infection, with associated morbidity and mortality. Patients with acute myeloid leukemia (AML) have qualitative and quantitative deficits in granulocytes predisposing to bacterial and fungal infections. Acute lymphoblastic leukemia results in qualitative deficits in lymphocytes, resulting in hypogammaglobulinemia and reduced cell-mediated immunity predisposing to certain bacterial and viral as well as fungal infections. Chemotherapeutic regimens often compound these deficits, result in prolonged periods of severe neutropenia, and disrupt mucosal barriers, further elevating infection risk. Despite advances in antimicrobial therapies and prophylaxis, acute leukemia patients with disease- and treatment-related immunosuppression remain at risk for life-threatening infection, including with resistant organisms, antimicrobial-related adverse events, and higher treatment costs. Additionally, our knowledge of infection risk and drug-drug interactions with new immune-targeted cancer therapeutics is evolving. Here, we review 3 areas in which standard practice is evolving as challenges arise and new experience is gained, including antibiotic use in febrile neutropenia, fungal prophylaxis, and use of targeted therapies.