The effects of ketamine, a drug used as an anesthetic and analgesic that also has psychotropic activity, are commonly attributed to its antagonism of the NMDA-type glutamate receptor. Chen et al., noting pharmacological and knockout data suggesting that blockade of NMDA receptor function was unlikely to account for all of ketamine’s actions, undertook a search for an alternative molecular substrate. In experimental models, ketamine-mediated anesthesia is associated with slow cortical oscillations (similar to the slow rhythm of deep sleep), leading the authors to investigate hyperpolarization-activated cyclic nucleotide–modulated (HCN1) cation channels, which mediate a hyperpolarization-activated cationic pacemaker current (Ih). Ketamine inhibited HCN1 channels expressed in human embryonic kidney (HEK) 293 cells, shifting the voltage dependence of channel activation as well as decreasing maximal current amplitude, at clinically relevant concentrations. Furthermore, consistent with its anesthetic effects, ketamine’s inhibition of HCN1 channels was stereoselective. In pyramidal neurons in cortical slices from wild-type mice but not mice lacking HCN1, ketamine inhibited a fast-activating Ih as well as eliciting membrane hyperpolarization and increased input resistance through inhibition of a constitutive Ih. Inhibition of dendritic Ih promotes the summation of excitatory postsynaptic potentials (EPSPs), an effect produced by ketamine in cortical pyramidal neurons of wild-type, but not HCN1-knockout, mice. Moreover, mice lacking HCN1 were less sensitive to the hypnotic effects of ketamine (assessed by loss of a righting reflex), as well as to the hypnotic effects of another intravenous anesthetic, propofol. The authors note that the combination of membrane hyperpolarization and enhanced synaptic efficacy produced by ketamine would be predicted to promote cortical oscillations and propose that blockade of HCN1 channels may contribute to ketamine’s actions through a mechanism that involves modulation of mechanisms involved in normal sleep.