ESAT-6 is a small secreted protein of unknown function from Mycobacterium tuberculosis that is of fundamental importance in virulence and protective immunity. A PSI-BLAST search has identified distant homologues of ESAT-6 in more tractable bacteria, including Bacillus subtilis, Bacillus anthracis, Staphylococcus aureus and Clostridium acetobutylicum. The genes for ESAT-6-like proteins often cluster with genes encoding homologues of B. subtilis YukA. I speculate that the ESAT-6-like and YukA-like proteins form a novel Gram-positive secretion system potentially driven by the FtsK/SpoIIIE ATPase domains in the YukA-like proteins. The way is now open to investigate this hypothesis in organisms that are easier to manipulate than pathogenic mycobacteria.