Normal cardiac impulse initiation occurs in the sinus node, in which gradual depolarization during phase 4 of the transmembrane potential results in attainment of threshold and initiation of action potentials that propagate to the rest of the heart. A current referred to as I_f initiates phase 4 depolarization. This current activates on hyperpolarization following termination of a preceding action potential. Although I_f initiates phase 4 depolarization, it is not the only current contributing to this: inward currents carried by Ca also play a role as does the Na/Ca exchanger. Counteracting these depolarizing influences are hyperpolarizing, outward currents carried by K. It is generally accepted that any net increase in inward current or decrease in outward current will increase phase 4 depolarization and cardiac rate. A key property of the pacemaker current is its modulation by autonomic influences. Catecholamines increase sinus rate by pathways initiated via their binding to beta-1 adrenergic receptors. This binding activates a G-protein coupled pathway in which adenylyl cyclase metabolizes ATP to cyclic AMP and P. The cyclic AMP binds to specific sites near the carboxy terminus of the channel, resulting in increased channel activation and an increased pacemaker potential. The effect of catecholamines to activate the channel is counteracted by muscarinic agonists, such as acetylcholine. The pathway here, too, is mediated via a G protein, with the net result being a braking of catecholamine-induced actions to accelerate rate. The property of the channel to be activated on hyperpolarization and to bind cyclic AMP has led to the nomenclature: hyperpolarization-activated, cyclic nucleotide-gated (or HCN) channel. There are four HCN channel isoforms; three, HCN1, HCN2 and HCN4 are in heart. HCN3 is in neural tissues. HCN4 and HCN1 contribute to impulse initiation in the sinus node. It has long been appreciated that in a variety of settings it might be desirable to either slow or speed heart rate. Major areas in which slowing of heart rate is often desirable include ischemic heart disease and a variety of post-surgical settings. A primary means for slowing rate has been beta-adrenergic blockade: yet this carries a potential for deleterious effects such as a loss of inotropy. For this reason, agents that act primarily on the HCN channel as a target to reduce I_f and slow rate on that basis have been viewed as desirable. In contrast to many other pharmacological agents, ivabradine has high selectivity and specificity for its target, the HCN channel. Importantly, in blocking the HCN channels that carry I_f, ivabradine suppresses but does not stop the sinus node pacemaker’s rate of firing. This reflects the contribution of the other ion channels mentioned above to the pacemaker potential, and also provides an important safety factor for ivabradine. Ivabradine’s clinical success to date provides an example of how highly targeted therapy can result in a risk/benefit advantage over other effective therapies. Another area of interest with regard to modulating I_f is in settings in which one might want to increase heart rate. The classic example here is the bradycardias that accompany sinoatrial node dysfunction or high degree atrioventricular block. Whereas the standard therapy over the past 60 years has become electronic pacemakers, over the last 5-10 years interest in biological pacemaking as an adjunct or alternative has increased. Although a variety of approaches were tried initially, current attempts focus largely on the use of viral and/or stem cell-based gene and cell therapies to deliver I_f current. The obstacles relating to the use of viral vectors or stem cells in humans constitute formidable challenges, yet preclinical research has proceeded briskly. This has demonstrated that the biological pacemaker is not only capable of providing baseline pacemaker function, but is autonomically responsive and can interact well with electronic pacemakers in a tandem mode of therapy.