2009 marks the 100th anniversary of the first description of Pneumocystis, an organism that was ignored for much of its first 50 years but that has subsequently been recognized as an important pathogen of immunocompromised patients, especially patients infected with human immunodeficiency virus (HIV). We present a patient with chronic lymphocytic leukemia who died from Pneumocystis pneumonia (PCP) despite appropriate anti-Pneumocystis therapy. Although substantial advances in diagnosis, treatment, and prevention of PCP have decreased its frequency and improved prognosis, PCP continues to be seen in both HIV-infected patients and patients receiving immunosuppressive medications. Pneumocystis species comprise a family of fungi, each of which appears to be able to infect only 1 host species. Pneumocystis has a worldwide distribution. Immunocompetent hosts clear infection without obvious clinical consequences. Pneumocystis has been identified in patients with other diseases such as chronic obstructive pulmonary disease, although its clinical impact is uncertain. Immunocompromised patients develop disease as a consequence of reinfection and possibly reactivation of latent infection. In patients with HIV infection, the CD4 count is predictive of the risk for developing PCP, but such reliable markers are not available for other immunocompromised populations. In the majority of patients with PCP, multiple Pneumocystis strains can be identified using recently developed typing techniques. Because Pneumocystis cannot be cultured, diagnosis relies on detection of the organism by colorimetric or immunofluorescent stains or by polymerase chain reaction. Trimethoprim-sulfamethoxazole is the preferred drug regimen for both treatment and prevention of PCP, although a number of alternatives are also available. Corticosteroids are an important adjunct for hypoxemic patients.