The plasma membrane is a semipermeable barrier composed of a lipid bilayer, which defines the boundaries between the intracellular and extracellular space. However, unlike the historical model of the “fluid mosaic” for the plasma membrane, in which integral membrane proteins are evenly distributed and free to diffuse, current knowledge suggests a more heterogeneous view of the plasma membrane in which proteins and lipids are clustered within specialized vesicular microdomains termed lipid rafts. This novel scenario for the cell surface has dramatic implications in cardiomyocytes, where the plasma membrane contributes to the correct exchange of electrolytes and ions essential for membrane depolarization and excitation-contraction coupling (ECC), which are at the basis for normal cardiac function. All major ion channels implicated in the regulation of the cardiac action potential mainly localize at the cell surface and the cellular membrane provides these specialized proteins with a formidable interface capable of regulating the cellular response and the modulation of ion channel function upon various stimuli from the extracellular and intracellular environment. The structural support, protein turnover, and functional regulation of ion channels on the plasma membrane occur through self renewal and molecular adaptation, which represent the molecular plasticity of the plasmalemma and its ability to maintain an adequate composition to ensure an adequate cellular performance and response.