Patients with Crohn's Disease and ulcerative colitis are increasingly treated with a host of immunomodulatory and immunosuppressive medications, including thiopurines and antibody-based biologic agents. Despite the known infectious complications associated with these therapies from the HIV and solid organ transplant literature, there are currently no well-defined concise guidelines to assist gastroenterologists and other physicians in the utility and indication for prophylaxis against Pneumocystis pneumonia and other infections in inflammatory bowel disease (IBD) patients. In this article, we discuss the evidence of various infections associated with immunocompromise in HIV/AIDS, organ transplantation, and in other immunocompromised states, and discuss the evidence for the efficacy and safety of various infectious prophylaxis protocols. In addition, we discuss the evidence for Pneumocystis and other infections in IBD patients treated with corticosteroids, azathioprine/6-MP, biologic agents and other therapies, and we present the case for various antibiotic (and antiviral) regimens to prevent such infections. Based on the review of the literature, this discussion represents a true call for guidelines for infection prophylaxis, to help guide gastroenterologists and all practitioners who care for the challenging population of IBD patients.