Typhoid toxin is a critical virulence factor of Salmonella Typhi, the cause of typhoid fever in humans 1. In experimental animals, this toxin can reproduce some of the acute, pathognomonic symptoms of typhoid fever. Typhoid toxin is a unique AB5 toxin in that it possesses two active ("A") enzymatic subunits linked to a single pentameric "B" subunit that targets these activities to specific cells and tissues 2. In addition, typhoid toxin has a rather unique biology since it is only expressed when S. Typhi is within mammalian cells, and it is subsequently exported to the extracellular environment by a specific vesicle trafficking process 3,4. This unique biology has hampered the ability to study the mechanisms by which the toxin is exported from the bacteria into the lumen of the Salmonella-containing vacuole since, until very recently, the only assay available to monitor toxin secretion was the visualization of the vesicle carrier intermediates in infected mammalian cells. Previous studies in our laboratory identified a gene, ttsA, which is essential for the secretion of typhoid toxin from bacterial cells 5. This gene, encoded within the same pathogenicity islet that contains the genes for the components of typhoid toxin, encodes a homolog of bacteriophage N-acetyl-β-D-muramidases. The recent discovery in our laboratory of the gene regulatory network that controls the expression of typhoid toxin within cells 6 has allowed the identification of in-vitro growth conditions that permit typhoid toxin expression. These growth conditions have allowed us to study the function of TtsA and, in the process, identified what we believe to be a novel mechanism of protein secretion described in our recent paper in Nature Microbiology.