Understanding the components of the immune system that contribute to host defense against infection is key to recognizing infections that are more likely to occur in an immunocompromised patient. In this review, we discuss the integrated system of physical barriers and of innate and adaptive immunity that contributes to host defense. Specific defects in the components of this system that predispose to particular infections are presented. This is followed by a review of primary immunodeficiency diseases and secondary immunodeficiencies, the latter of which develop because of a specific illness or condition or are treatment-related. The effects of treatment for neoplasia, autoimmune diseases, solid organ and stem cell transplants on host defenses are reviewed and associated with susceptibility to particular infections. In conclusion, an approach to laboratory screening for a suspected immunodeficiency is presented. Knowledge of which host defects predispose to specific infections allows clinicians to prevent, diagnose, and manage infections in their immunocompromised patients most effectively.