Phosphorylation or dephosphorylation of an aspartate regulates the output activity of the response regulator of two-component signaling systems. Signal input in these systems is dependent on signal-transducing kinases, which can respond to a variety of signal ligands and, in some cases, to small phosphorylated metabolic intermediates. The kinase component of many two-component signaling systems also displays a response regulator-phosphate phosphatase activity that inactivates the response regulator in response to signals. Newly discovered kinase-independent phosphatases allow additional signals to influence the extent of response-regulator phosphorylation. Such phosphatases are prevalent in signal transduction systems controlling complex processes, such as the initiation of development in microorganisms.