Infections caused by Pneumocystis jirovecii (PJ), an opportunistic fungus, can have major consequences in terms of morbidity and mortality. These infections occur mainly in immunocompromised patients and are known for their pulmonary tropism (Pneumocystis pneumonia, PCP). Epidemiologically, more PJ infections are now encountered in the non-HIV (human immunodeficiency virus) population than in HIV-infected individuals. While prevention modalities have been studied in HIV-infected populations, evidence is scarce in non-HIV patients. The decision to prescribe prophylaxis for PJ requires assessment of the clinical context, as well as existing risk factors that may predispose an individual to develop PCP. Few indicators exist that are sufficiently sensitive and specific to predict the occurrence of PCP. While certain underlying conditions have clear recommendations for prophylaxis such as solid organ transplant recipients, evidence is scarce. The decision to use prophylaxis must be made while taking into consideration the overall context of the patient.