Posaconazole is a triazole with broad spectrum of activity against multiple fungi including members of the fungal order Mucorales. This activity has been shown both in clinical and in vitro studies, which are critically reviewed here. It has become very popular in prophylaxis in acute myelogenous leukemia (AML) induction and in the graft-versus-host disease (GVHD) settings after 2 recent prospective trials that showed advantage of posaconazole prophylaxis compared to fluconazole or itraconazole. In this report, 2 patients are presented, in whom, despite posaconazole prophylaxis, invasive and ultimately fatal Rhizopus pulmonary infections developed. These cases are similar to a previously reported case of Rhizopus infection in a stem cell transplant recipient who also received posaconazole, indicating a potential newly recognized pattern of breakthrough infections in patients receiving posaconazole prophylaxis.