Most membrane-anchored histidine kinases (HKs) of bacterial two-component systems (2CSs) contain an extracellular input domain that is thought to be responsible for sensing an environmental cue. By contrast, intramembrane-sensing HKs (IM-HKs) lack a sensory domain and cannot perceive their stimuli directly. Instead, an N-terminal signal transfer region, consisting solely of two transmembrane helices, presumably connects the IM-HKs with accessory membrane proteins that function as the true sensors. This intermolecular signal transfer, in combination with intramolecular signal conversion, provides HKs with versatile signaling relays to connect, integrate, and amplify external signals from different sensory inputs ultimately to modulate the activity of the corresponding kinase domain.