Children on immunosuppressive therapy for cancer or organ transplantation are very similar to those with primary immunodeficiency in that all are highly predisposed to infection with all types of pathogens-ie, bacteria, viruses, fungi, and parasites-and are highly likely to experience the reactivation of microbial agents, particularly viruses, while they are immunosuppressed. For this reason, early recognition and treatment are critical for optimal chances of survival and minimal morbidity. The selection of initial empiric therapy for these patients when febrile is based on the type of immune suppression (eg, neutropenia and cellular immunity) and other predisposing factors such as the presence of central venous lines (CVLs). Much of our clinical approach to prophylactic and definitive antimicrobial therapy for children with cancer and suspected infection comes from our experiences in managing children with primary immunodeficiency. For this reason, the present review examines aspects of management of all patients with primary or acquired immunodeficiency. Consistent infections in all of these patients include bacteremia in those with CVLs, Pneumocystis jirovecii pneumonia, primary and reactivation infection with herpes group viruses, and opportunistic fungi.; Some infections in well-defined groups of immunosuppressed hosts are frequent enough to warrant prophylactic therapy; in most cases, the duration of such therapy is well defined. Excessive continuation is likely to lead to colonization and infection with antibiotic-resistant organisms. When antimicro-bial therapy is used for defined infections, the use of the highest dosages considered safe and longer durations are warranted.