Pneumocystis jiroveci pneumonia remains one of the major worldwide contributors to the morbidity and mortality of those with HIV infection. The mainstay of therapy for treatment is trimethoprim-sulfamethoxazole (TMP-SMX); however TMP-SMX may be associated with significant side effects and intolerability. In addition, TMP-SMX has a moderate pill burden with three- to four-times daily dosing schedule. Patients unable to tolerate TMP-SMX are confronted with either parenteral therapy or other oral agents that may be less efficacious or are associated with potential serious adverse reactions. Pafuramidine (DB289) is an orally bioavailable prodrug of furamidine (DB75), an investigational diamidine that is less toxic than previous diamidines such as pentamidine. To date, human trials suggest that pafuramidine is well tolerated overall and has clinical activity against Pneumocystis pneumonia. In this article, we review the available data for the use of pafuramidine in Pneumocystis pneumonia.