The Rickettsiales, a genetically diverse group of the alpha-Proteobacteria, include major mammalian pathogens, such as the agents of epidemic typhus, scrub typhus, ehrlichioses and heartwater disease. Sequenced genomes of this bacterial order have provided exciting insights into reductive genome evolution, antigenic variation and host cell manipulation. Recent results suggest that human pathogens emerged relatively late in the evolution of the Rickettsiales. Surprisingly, there is no association between pathogenicity and the acquisition of novel virulence genes. Here, we explore the genomic differences between members of the Rickettsiales and ask what are the changes that enable infectious agents to emerge from seemingly harmless bacteria.