The cloning of K(Ca)2 channels revealed three subtypes, with each displaying distinct but partially overlapping expression distributions in the mammalian CNS and periphery. Activation of K(Ca)2 channels leads to membrane hyperpolarization and inhibition of action potential firing. Block of K(Ca)2 channels has been suggested as a novel target for cognitive enhancement, depression, myotonic muscular dystrophy and heart arrhythmias. It is clear however, that blockers selective for individual K(Ca)2 channel subtypes would be required to be therapeutically useful. K(Ca)2 channel current is blocked by apamin, with the bee venom toxin being unusual in displaying some selectivity between K(Ca)2 channel subtypes. This suboptimal selectivity is not sufficient to be therapeutically useful and the toxin has been shown in vivo to have a very narrow therapeutic window. Mutational and molecular modelling studies of the K(Ca)2 channels are beginning to determine how selective block might be achieved. Mutagenesis has indicated the importance of the outer pore region and the extracellular loop between transmembrane domains S3 and S4 for block of K(Ca)2 current by apamin. Mapping the sequence of transmembrane domains S5, pore helix and S6 onto the crystal structures of KcsA, MthK and Kv1.2 has provided an approximation of the pore structure. This approach has allowed structural modelling of the interactions between toxins and channel, demonstrating that the toxins that show little discrimination between K(Ca)2 channel subtypes interact with the outer pore and around the K(+) selectivity filter. We present the structural modelling of the interaction of apamin and K(Ca)2.2, which is superimposed onto the crystal structure of Kv1.2. This has shown that apamin interacts only with the outer pore and does not come into contact with channel's selectivity filter. It is clear that by comparing how different toxins interact with each K(Ca)2 channel subtype, a detailed picture will be generated that will aid the development of more specific K(Ca)2 channel blockers.