The mammalian heart has remarkable intrinsic rhythmic properties. It is widely agreed that spontaneous diastolic depolarizations (DDs) in sino-atrial node cells (SANCs) periodically initiate action potentials (AP), which set the rhythm of the heart.1 Efforts to understand the origin of the pacemaker activity have a lengthy history and the subject has, for various technical reasons, proved somewhat intractable. Any explanation of pacemaker activity must address three central issues. First, how do DDs arise? Second, what determines their periodicity? And third, how is the rate modulated? In this issue of Circulation Research, Vinogradova and her colleagues2 offer some novel observations that go far toward explaining these issues. The article, which is the most recent of an exhaustive series of experiments from Dr Lakatta’s group, offers an explanation of the control of pacemaker activity based on both biophysical and biochemical observations, integrated with appropriate mathematical modeling (see supplement). This work depends on the central idea that pacemaking involves complex interactions within a multi-molecular complex that resides in both sarcolemmal and SR membranes. An attractive feature of this work is that it suggests a number of interesting structural and functional avenues of investigation that are amenable to contemporary biophysical methods, particularly confocal microscopy. No single current by itself is responsible for DD. It is the sum of at least 6 ionic currents: Ikr, If, Ist, ICa (with two components: ICa-T and ICa-L), and INCX. In a previous study, Bogdanov et al4 show that sodium– calcium exchanger (NCX) is of crucial importance to maintaining pacemaker activity. A more complete discussion of the temporal relationships between these various currents is reviewed elsewhere.5 Dr Lakatta’s group have emphasized the importance of the involvement of intracellular Ca (particularly SR Ca ) in the regulation of pacemaker activity. Although their work is extremely provocative, it is worth pointing out that this view of pacemaker activity is not unanimous. It is in principle possible to obtain pacemaker activity with only three timeand voltage-dependent currents.12 The implication of this is that Ca homeostasis need not be involved in pacemaker activity. Moreover, recently Lancaster et al13 have pointed out that smaller centrally located SANCs continue to pace in the presence of ryanodine. Clearly the involvement of Ca homeostasis in pacemaker activity is controversial.