A biological pacemaker based on the HCN gene family, the molecular correlate of the native cardiac pacemaker current, holds promise of enhancing or supplanting current electronic pacemakers by providing autonomic responsiveness of cardiac rate. Gene-based and cell-based delivery of the HCN gene have been employed to produce biological pacemakers. This article reviews efforts to date to create gene- and cell-based biological pacemakers, using both the HCN gene family and other approaches, and discusses what is known about the autonomic responsiveness in each case. Possible future refinements to an HCN based biological pacemaker also are discussed.