Pacemaking, a most fundamental cardiac function, has long occupied a central place in physiological research. What makes the heart “beat”? Spontaneous activity originates in SAN pacemaker cells thanks to a distinctive phase of their action potentials, the diastolic depolarization (DD). In the late 70s, a new ionic current (“funny”, I_f current), was identified in pacemaker tissue. Its unusual property (an inward current activated on hyperpolarization) introduced a novel concept in pacemaker physiology in strong contrast with existing models. Subsequent studies of I_f and its molecular correlates, the HCN channels, established their key role in DD generation and in autonomic modulation of heart rate. Pacemaking is however a complex cellular process, and other players are known to contribute, including the Ca-clock mechanism, the sustained inward current, the ACh-activated K current, the Cav1.3 channel; this latter player, expressed exclusively in pacemaker cells, has distinctive properties and according to recent data fully controls, together with HCN4 channels, adrenergic rate modulation. Although specific functional aspects may require fewer mechanisms, the whole pacemaking function emerges from the coordinated action of many players. This raises two questions: 1) why several players for a single function? 2) if one function needs several players, how extensive must the repertoire be to support the extraordinarily large number of cellular functions?

The answer to 1) is “robustness”: redundancy ensures that backup mechanisms compensate when one or more components fail. The answer to 2) is “multifunctionality”: many molecular players serve diverse roles across tissues. f/HCN channels, for example, are expressed far beyond cardiomyocytes and participate in processes as varied as sensory transduction, hormone secretion, gastrointestinal motility, osteoclastogenesis, immune cell activation, mitochondrial respiration, even stem‑cell cycle control and early embryonic development, and others.

The lessons learned from these studies illustrate a general principle: biological functions arise from combinatorial partnerships among mechanisms, rather than from a simplistic “one gene–one function” paradigm.