(1) Why do we need to know anything about these patients? Regardless of their specialties, physicians are increasingly confronted with the side effects of therapies that cause varying degrees of immunosuppression: chemotherapy and stem cell transplantation for cancer, solid organ transplantation, and therapies for autoimmune and rheumatological diseases. The management of these patients is increasingly being returned to community-based physicians. The infectious disease clinician is faced with major challenges. (2) The possible etiologies of infections are diverse; they range from common bacterial and viral pathogens that affect the entire community to opportunistic pathogens that are clinically significant only for immunocompromised hosts. (3) Inflammatory responses are impaired by immunosuppressive therapy, and this results in diminished clinical and radiological findings. Thus, an early diagnosis is much more difficult, but it is the key to successful therapy. Invasive diagnostic procedures are often required. (4) Antimicrobial therapies are often more complex in these patients versus other patients because of the urgency of empiric therapy and the frequency of drug toxicity and drug interactions. (5) Drug interactions and drug toxicity are common. The initiation or cessation of antimicrobial therapies may alter the levels of calcineurin inhibitors, antifungal agents, and other drugs. (6) Graft rejection and graft-versus-host disease may be confused with infections. (7) New pathogens and new manifestations of infections in compromised hosts are also problems: a Pathogens common to individuals with prolonged defects in their cellular immune function (human immunodeficiency virus) and to neutropenic hosts [Rhodococcus, Cryptosporidium, and Penicillium species; Mycobacterium species (eg, Mycobacterium avium complex); and Scedosporium] have been identified in transplant recipients. b Antimicrobial resistance is a major problem [vancomycin-resistant Enterococcus; methicillin-resistant Staphylococcus aureus; Pseudomonas, Stenotrophomonas, and Burkholderia species; fungi (both yeasts and molds); and ganciclovir-resistant cytomegalovirus]. c There are few therapies for newer viral pathogens (eg, human herpesvirus 6, human herpesvirus 8, and BK virus) and common respiratory viruses (eg, respiratory syncytial virus, adenoviruses, and Metapneumovirus). d Patients from endemic regions may have parasites (eg, Chagas disease and Leishmania).