Four different hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel isoforms have been cloned (HCN1-4). They can be distinguished by differing sensitivity to modulators such as cAMP, different V1/2 values of activation and different activation kinetics. Even though they are structurally similar to Kv channels they are activated by strong hyperpolarizing voltages rather than depolarizing voltages. As such the channels are active at or around the resting potential and contribute to pacemaker activity both in the heart and CNS. There is considerable overlap in the expression of these isoforms in different tissues and it is highly likely that they can form heteromultimers. Altered HCN channel expression has been implicated in increased neuronal hyperexcitability following seizures and may represent a novel drug target for the treatment of seizure-evoked epilepsy. HCN channels also appear to have a role in some models of neuropathic pain where the spontaneous firing of damaged nerves and therefore the sensation of pain can be alleviated by the selective HCN blocker ZD7288.