The molecular targets and neural mechanisms by which general anaesthetics mediate important clinical actions remain enigmatic. HCN channels underlie the hyperpolarization-activated cationic currents that contribute to neuronal pacemaker currents and determine synaptic integrative properties. We have found that HCN1 and HCN2 subunits, which are prominently expressed in the CNS, are differentially modulated by multiple classes of anaesthetics at clinically relevant concentrations. In this respect, inhalational anaesthetics appear to modulate both subunits via a similar mechanism (i.e., they stabilize channel closed state) but the predominant manifestation of that action (a negative shift in V½ for HCN1 and a decreased current amplitude for HCN2) is determined by allosteric properties imposed by individual subunit C-terminal domains; experimental and computational studies verify these different forms of inhibition in various neuronal settings and reveal their quantitatively distinct actions on synaptic integration. We have also found that HCN1-containing channels are inhibited by propofol and ketamine, two distinct classes of intravenous anaesthetic. In this case, inhibition is characterized by both a shift in V½ and decreased current amplitude; these actions are recapitulated in cortical pyramidal neurons where anaesthetic-mediated inhibition leads to enhanced dendritosomatic synaptic summation, and they are absent in those cells from HCN1 knockout mice. Importantly, HCN1 knockout mice have diminished sensitivity to the hypnotic effects of these anesthetics. We propose that enhanced synaptic integration resulting from HCN channel inhibition in cortical pyramidal neurons may contribute to the cortical synchronization that accompanies anaesthetic-induced hypnosis.