Several manifestations of Sinus Node Disease involve improper impulse generation/ propagation and impaired maintenance of normal sinus rhythm. The established role of funny/HCN4 channels in pacemaker activity generation and normal rate control makes them natural candidates in the search for potentially arrhythmogenic ion channel dysfunctions. Along with the wealth of existing evidence supporting the role of funny/HCN4 channels in the physiological control of rate (for review see DiFrancesco, 2010), experimental data have also been collected showing that a defective funny current can be associated with rhtyhm abnormalities. For example, results from cardiac-specific, Tamoxifen-inducible HCN4 knockout mice show that specific HCN4 deletion in cardiac tissue leads to progressive bradycardia and cardiac arrest after about 5 days; interestingly, death does not occur because of sinus arrest but because of AV block, suggesting a previously unrecognized role of HCN4 channels in AV rhythm and/or AV conduction that requires fuller investigation (Baruscotti et al., 2011). More direct evidence for the association between funny/HCN4 channels and rate is provided by the HCN blocker ivabradine, the only specific “heart rate-reducing” agent commercially available today and used in the therapy against angina. Heart rate reduction is a therapeutic target in ischemic heart disease and heart failure. By selectively blocking f-channels, ivabradine reduces heart rate and clinical work showns that this occurs without cardiovascular side-effects, highlighting the therapeutic relevance of funny channel-based pacemaking and its pharmacological control. Because of its pure rate-reducing properties, it is to be expected that ivabradine can be useful against tachycardia; indeed, several recent observations indicate that ivabradine can be succesfully used in the treatment of adult and pediatric forms of Inappropriate Sinus Tachycardia (Femenia et al., 2012). A direct demonstration of the involvement of defective HCN4 channels in cardiac arrhythmias comes from the finding that specific HCN4 mutations leading to loss-of-function defects are associated with arrhythmias and more specifically with bradycardia. Four arrhythmia-related mutations have been described so far in HCN4 channels. The point mutation S672R in the CNBD of HCN4 channels was found to cause asymptomatic sinus bradycardia in 15 out of 27 members of a large 3-generation family (Milanesi et al., 2006). According to functional studies, S672R is a loss-of-function mutation inducing a negative shift of about 5 mV of the funny current activation curve, when expressed in heterozygous conditions. Therefore, since shifting the funny current activation curve to the negative direction is the typical action of parasympathetic stimulation, in the case of the S672R mutation bradycardia is caused by a constitutive change of channel properties mimicking cholinergic-induced channel inhibition. Other arrhythmia-related loss-of-function HCN4 mutations were described in the C-linker, such as L573X, a mutation found in a single patient which generates a truncated protein lacking the CNBD (Schultze-Bahr et al., 2003), and D533N, a point mutation reported to depress membrane trafficking (Ueda et al., 2004). In the first case the patient suffered from bradycardia, chronotropic incompetence and atrial fibrillation; since this patient was investigated individually, no inheritance could however be evaluated. In the second case the report referred to a small family with a complex array of rhythm disturbances including severe bradycardia, syncope, LQT and torsade des pointes; however, a full functional investigation of the correlation between HCN4 mutation and phenotype was not performed. A fourth mutation associated with familial asymptomatic bradycardia (G480R) was reported in the pore region of the channel (Nof et al., 2007). The mean heart rate of affected family members was lower than 55 bpm, compared with 63 bpm of non-affected individuals. Functional studies revealed that this mutation reduces the size of the diastolic funny current by decreasing channel synthesis and traffiking, and shifts the current activation curve to the negative direction. The mutation modifies the GYG selectivity sequence typical of K+-permeable channels; surprisingly however, the authors did not find a significant change in the Na/K permeability ratio (Nof et al., 2007). These data suggest the existence of a general mechanism for HCN4-linked arrhythmias and justify the tentative prediction that more HCN4 mutations, yet to be identified, are likely to contribute to different forms of inheritable arrhythmias whose substrate is the sinus node and conduction system.