Yersinia pestis, the causative agent of bubonic plague, is one of the most lethal pathogens in recorded human history. Today, the concern is the possible misuse ofY. pestisas an agent in bioweapons and bioterrorism. Current therapies for the treatment of plague include the use of a small number of antibiotics, but clinical cases of antibiotic resistance have been reported in some areas of the world. Therefore, the discovery of new drugs is required to combat potentialY. pestisinfection. Here, the crystal structure of theY. pestisUDP-glucose pyrophosphorylase (UGP), a metabolic enzyme implicated in the survival ofY. pestisin mouse macrophages, is described at 2.17 Å resolution. The structure provides a foundation that may enable the rational design of inhibitors and open new avenues for the development of antiplague therapeutics.