Heat-labile enterotoxins (LTs) of Escherichia coli are closely related to cholera toxin (CT), which was originally discovered in 1959 in culture filtrates of the gram-negative bacterium Vibrio cholerae. Several other gram-negative bacteria also produce enterotoxins related to CT and LTs, and together these toxins form the V. cholerae-E. coli family of LTs. Strains of E. coli causing a cholera-like disease were designated enterotoxigenic E. coli (ETEC) strains. The majority of LTI genes (elt) are located on large, self-transmissible or mobilizable plasmids, although there are instances of LTI genes being located on chromosomes or carried by a lysogenic phage. The stoichiometry of A and B subunits in holotoxin requires the production of five B monomers for every A subunit. One proposed mechanism is a more efficient ribosome binding site for the B gene than for the A gene, increasing the rate of initiation of translation of the B gene independently from A gene translation. The three-dimensional crystal structures of representative members of the LT family (CT, LTpI, and LTIIb) have all been determined by X-ray crystallography and found to be highly similar. Site-directed mutagenesis has identified many residues in the CT and LT A subunits, including His44, Val53, Ser63, Val97, Glu110, and Glu112, that are critical for the structures and enzymatic activities of these enterotoxins. For the enzymatically active A1 fragment to reach its substrate, receptor-bound holotoxin must gain access to the cytosol of target cells.