text: The increased complexity of the phosphorelay system compared to orthodox two-component signaling provides additional opportunities for regulation and improves the specificity of the response. Although there is very little cross-talk between orthodox two-component systems, phosphorelays allow more complex signaling pathways; examples include a bifurcated pathway with multiple downstream outputs, as in the case of the Caulobacter crescentus ChpT HPt involved in cell cycle regulation, or, alternatively, pathways in which more than one histidine kinase controls a single response regulator, such as the sporulation pathway in Bacillus subtilis, which can give rise to complex temporal variations. In some known cases, there is an additional form of regulation in phosphohistidine phosphatase enzymes that act on HPt, such as the Escherichia coli protein SixA which targets ArcB.