Sinus node dysfunction is commonly known as sick sinus syndrome (SSS). It is a frequent cause of arrhythmias, especially in elderly patients but it can also occur at all ages, including in the newborn. Sinus node dysfunction is the major cause necessitating pacemaker implantation and accounts for approximately half of all patients requiring a permanent pacemaker. SSS may be due to different causes e.g. arterial hypertension, coronary artery disease, trauma, infectious diseases, drugs, electrolyte imbalances or familiar diseases. Manifestations include severe sinus bradycardia, sinus pauses or arrest, sinus node exit block, chronic atrial tachyarrhythmias, alternating periods of atrial bradyarrhythmias and tachyarrhythmias, and inappropriate responses of heart rate during exercise or stress. Besides disease-associated reasons, one reason for developing idiopathic sick sinus syndrome are mutations in genes coding for ion channels involved in pacemaking. The role of the cardiac sodium channel encoded mainly by SCN5A (Nav1.5) in sino-atrial node depolarisation is unclear. Mutations have been identified in patients with sinus node dysfunction. Consistent with the electrophysiology, Nav1.5 is present in atrial muscle and the periphery of the node but absent from the center of the sino-atrial node. Despite this, knockout of Nav1.5 in a mouse model results in bradycardia, a delay in sinus node conduction time, and block of sinus node conduction. Knockout of the Na-channel β2 subunit also results in bradycardia and sinus node dysfunction. Recently, various brain-type Na channels, including Nav1.1, have also been shown to be expressed in cardiac myocytes. Nav1.1, in contrast to Nav1.5, is present in the node as well as the atrial muscle and seems to play a functional role in proper sinus node function. In the working myocardium the principal calcium channel isoform is Cav1.2 responsible for ICa,L. But, in the node, Cav1.3 seems to be the major player. Knocking out Cav1.3 causes bradycardia and sinus dysfunction, linked to abolition of the major component of ICa,L. In addition, knockout of Cav3.1, that is carrying ICa,T, causes bradycardia , slows the intrinsic heart rate, and prolongs sinus node recovery time. HCN channels (HCN1, 2, and 4) that are highly expressed in the node are responsible for I_f. The principal channel in the node is HCN4. HCN4 knockout is lethal at embryonic stages, but the embryos exhibit bradycardia accompanied by dramatic decrease in cardiac I_f. Knockout of the HCN2 gene results also in a reduction of I_f in vitro but in vivo there is no significant bradycardia, but sinus dysfunction is observed. Gap junction channels, composed of connexins, are responsible for electric coupling between cells. However, in contrast to atrial muscle, electric coupling within the node is poor and conduction is slow. This protects the pacemaker from the hyperpolarizing influence of the surrounding atrial muscle. There is evidence that electric coupling is stronger in nodal periphery because of interdigitations of atrial and nodal cells in the periphery and it has been suggested that this permits the node to drive the surrounding atrial muscle and at the same time to be protected from the hyperpolarizing influence of the atrial muscle. In Cx40 knockout mice, there is evidence of bradycardia, sinus node exit and entry block, and a prolongation of the sinus node conduction time. SSS is caused by different conditions with multiple causes. Fibrosis, ion channels, variants related to heart failure, ageing and AF are determinants. Assuming that these conditions cause ‘electric remodelling’, manipulation of ion channel gene expression in the node could be a powerful therapeutic tool protect and restore proper nodal function. Therefore research has put much interest in generating ‘biopacemakers’ by manipulation of ion channel genes and gene expression.