It is generally agreed that the major role played by the funny current in the heart relates to the generation of normal, physiological pacemaker activity in the cardiac pacemaker region, the sinoatrial node (SAN), and to the control of heart chronotropism, although the exact degree by which funny channels contribute to govern pacemaking within the framework of the more complex set of partecipating mechanisms is still strongly debated. Several experimental and theoretical results provide evidence for the role of If in pacemaking. Among these results, of practical impact are applications of the concept of funny channel-based pacemaking of clinical relevance; starting from molecular/cellular properties, these applications translate the concept to the more integrated level of cardiac health in a clinical setting. In a first example, the correlation between expression of funny channels, or more specifically of their molecular correlates HCN channels, and spontaneous activity is the basis for proof-of-concept development of “biological pacemakers”. In cell-based models, it has been shown that spontaneously beating ESC-derived myocytes, known to express If, can pace cultures of neonatal rat cardiac myocytes and generate ectopic rhythms when injected in the ventricle of animal models after ablation of the AV node (Rosen et al., 2011). The aim of these protocols is to develop potential alternatives to electronic pacemakers. In a second example, a most important clinical exploitation of funny channel properties relates to the pharmacological control of heart rate. Many funny channel-targeted drugs have been developed so far, among which ivabradine, the only drug marketed today for use in chronic stable angina and heart failure. Ivabradine is a specific blocker of funny channels, a property leading to a therapeutically useful “pure” heart rate slowing action (DiFrancesco & Camm, 2004). Ivabradine-induced block of funny channels has been analyzed in detail and shown to be characterized by a marked “use dependence”, which may favour increased drug efficiency, as a rate-reducing agent, at high heart rates (tachycardia). In a third example, several studies have shown recently that mutations in HCN4, the HCN isoform most highly expressed in pacemaker tissue, are associated with inheritable forms of arrhythmias and have provided growing evidence for a role of dysfunctional funny channels in rhythm disorders. Reported HCN4 mutations are associated with asymptomatic and symptomatic sinus bradycardia, tachycardia-bradycardia syndrome, AV node block, atrial fibrillation and contribute to more complex arrhythmias (Baruscotti et al., 2010). The above studies, together with evidence from studies of HCN knockout mice (Bucchi et al., 2012) and data from the clinical use of ivabradine (Cappato et al., 2012), indicate that the role of funny channels need not be confined to control of physiological pacemaker activity of the SAN, but can also be relevant to maintenance of normal rhythmic activity in a broader context. If has a recognized pathophysiological role in heart failure, since transcription of HCN channels increases in hypertrophied ventricles of failing hearts and predisposes to enhanced ventricular automaticity. Also, reduction of funny channel expression in pacemaker cells of cardiac-specific, inducible HCN4 KO mice eventually leads to lethal AV block, as well as to the expected slowing of SAN rate, suggesting a previously unsuspected role of HCN4 in AV node activity and stimulus conduction (Baruscotti et al., 2011). Finally, ectopic beats originating in pulmonary veins are recognized sources of atrial arrhythmias and can initiate AF. It is interesting to note that funny channel-expressing pacemaker cells are present in pulmonary veins, and can contribute to ectopic beat generation and arrhythmogenesis (Chen et al., 2009). This implies that dysfunctional funny channels and/or altered If tissue distribution may also contribute to atrial arrhythmias and AF. My talk will be devoted to review recent reports illustrating how candidate gene screening of the Hcn4 gene in families with arrhythmias has identified several causative HCN4 mutations in different types of rhythm disorders, and to discuss the perspective of future research in this area.