The current kinetics of two-pore domain potassium (K2P) channels resemble those of the steady-state K(+) currents being active during the plateau phase of cardiac action potentials. Recent studies support that K2P channels contribute to these cardiac currents and thereby influence action potential duration in the heart. Ten of the 15 K2P channels present in the human genome are sensitive to variations of the extracellular and/or intracellular pH value. This review focuses on a set of K2P channels which are inhibited by extracellular protons, including the subgroup of tandem of P domains in a weak inward-rectifying K(+) (TWIK)-related acid-sensitive potassium (TASK) and TWIK-related alkaline-activated K(+) (TALK) channels. The role of TWIK-1 in the heart is also discussed since, after successful expression, an extracellular pH dependence, similar to that of TASK-1, was described as a hallmark of TWIK-1. The expression profile in cardiac tissue of different species and the functional data in the heart are summarized. The distinct role of the different acid-sensitive K2P channels in cardiac electrophysiology, inherited forms of arrhythmias and pharmacology, and their role as drug targets is currently emerging and is the subject of this review.