In the genus Bordetella several important human and animal pathogens are classified with B. pertussis, the etiological agent of whooping cough, being medically the most relevant. In these bacteria expression of the most important virulence factors including several toxins, adhesins and colonization factors is controlled by a single master regulatory two-component system, the BvgS/BvgA system. This system represents a paradigm of a complex phosphorelay system that mediates a fine-tuned transcriptional response resulting in different expression levels of virulence factors during different stages of the infection process. In this chapter the current knowledge about signal perception and the molecular basis of differential gene expression controlled by a single two-component system is discussed.