Infections are common in patients with hematologic neoplasms and following allogeneic hematopoietic transplantation. Neutropenia and defects in adaptive B-cell-mediated immunity and/or lack of splenic function predispose patients to a host of diverse and often serious infections. It is important to recognize that patients who undergo treatment for hematologic neoplasms may have mixed immune defects, and their vulnerability to infection may continue to change, in part as a reflection of the dynamic developments in the practice of oncology. The main obstacle in providing targeted, evidence-based antimicrobial treatment is the unpredictable results of even the new generation of diagnostic assays. A definite diagnosis for most end-organ opportunistic diseases requires tissue samples that are seldom available. Because immune defects may coexist, empirical therapy is directed toward a wide spectrum of pathogens. Real-time information about innate and adaptive immune functions and the role of acute and chronic phase molecules may improve target-specific therapy.