Yersinia pestis, the causative agent of pneumonic plague, evolved from the mild enteric pathogen Yersinia pseudotuberculosis. To understand how Y. pestis evolved to cause plague, Zimbler et al. used a mouse model to compare ancestral and modern strains of Y. pestis. Ancestral strains were capable of causing pneumonic plague, but only if they contained the gene encoding the Pla protease, which is present in all modern strains. Notably, introduction of pla into an ancestral strain naturally lacking the gene conferred the ability to cause pneumonic plague, indicating that Pla acquisition was sufficient for ancestral Y. pestis to cause severe respiratory disease. Furthermore, modern Y. pestis strains also acquired a single amino acid substitution in Pla that increased bacterial invasion of other organs — a characteristic of bubonic plague — indicating that Y. pestis evolved to cause pneumonic plague before adapting to cause bubonic plague.