HCN4 is the major Hyperpolarization-activated Cyclic Nucleotide-gated ion channel in the mammalian heart. They are voltage-gated, cation channels, typically closed at resting and depolarized membrane potentials. The action of HCN4 is essential for the rhythmicity of the heart beat as well as controlling the strength of the contraction. HCN4 is expressed in the heart and brain, but significantly, not in the retina. The side effects of many anti-arrhythmic drugs include visual disturbances; a selective HCN4 blocker would potentially slow the heart rate without affecting vision. Safety screening, to detect undesirable action on HCN4 channels, is essential to assess the cardiac liability of new drug submissions.