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Critically ill children with infection require the timely institution of the appropriate antimicrobial medications based on the most likely pathogens. Sepsis is a relatively common and potentially life-threatening bloodstream infection. Recognizing its early clinical manifestations, understanding its epidemiology, and instituting the appropriate antimicrobials in a timely manner hold the potential to improve outcomes. Toxic shock syndrome, endocarditis, and Lemierre syndrome represent other infections that may compromise hemodynamics and result in critical illness. Children with necrotizing fasciitis often present critically ill and require emergent surgical debridement. Central nervous infections including bacterial meningitis, encephalitis, and ventricular shunt infections are also commonly encountered in the pediatric intensive care unit and may be associated with a significant risk of death and substantial morbidity. Pneumonia and other pulmonary infections may be caused by a variety of pathogens. Empyema is an established complication of infectious pneumonia that often requires urgent evaluation and drainage in children with worsening respiratory and/or cardiovascular status. Although the specific pathogen and the site of infection (e.g., bloodstream, brain, lungs) clearly influence the severity of illness, the ability of the host to respond to an infection is also important. For example, immunocompromised children including those with malignancy and recipients of organ and hematopoietic cell transplants are not only at increased risk for infection but also for worse outcomes. Finally, there are a few relatively less common and travel-related infections such as rickettsial disease, viral hemorrhagic fevers, malaria, and tuberculosis that are relevant to the practice of pediatric critical care medicine.