Bordetella pertussis and the closely related species B. parapertussis and B. bronchiseptica colonize the respiratory tract and cause related diseases in man or mammalian species, respectively. Expression of virulence factors by these pathogens is coordinately regulated by the BvgAS two-component system according to changes in the growth conditions. Signal transduction by the BvgAS system is characterized by a complex His-Asp-His-Asp phosphorelay. This system controls the expression of two distinct subsets of genes either in a positive (vag genes) or in a negative (vrg genes) manner. Most of the known virulence factors such as several toxins and adhesins are encoded by vag genes, whereas the functions of most vrg genes and the biological significance of the vrg regulon are not yet clear. This review discusses the current knowledge about the molecular mechanisms of virulence regulation and their relevance for infection by these respiratory pathogens.