The heart is a complex multicellular muscle that coordinates its electrical excitability and contraction through membrane ion channels and transporters. These marvelous intrinsic membrane proteins orchestrate the many phases of the cardiac action potential and its surface equivalent, the electrocardiogram. Most of the important ion channels and transporters have been cloned, allowing structural insight into their molecular machinery. Cardiac disease is reflected in primary or secondary changes in the function or distribution of these membrane proteins. Most cardioactive drugs target these proteins, and some of the drugs play an important role in the modern treatment of cardiac arrhythmias, ischemia, and heart failure. This article introduces these critical proteins. Drugs that directly block critical ion channels or transporters, such as those for Na+, K+, and Ca2+, also have serious undesirable effects, including proarrhythmia. Consequently, several critical clinical questions arise from this discussion. Future drug development may need to target other channels or modulate channel function in different ways...