Cardiac arrhythmias continue to pose a major medical challenge and significant 
public health burden. Atrial fibrillation, the most prevalent arrhythmia, 
affects more than two million Americans annually and is associated with a 
twofold increase in mortality. In addition, more than 250,000 Americans each 
year suffer ventricular arrhythmias, often resulting in sudden cardiac death. 
Despite the high incidence and societal impact of cardiac arrhythmias, presently 
there are insufficient insights into the molecular mechanisms involved in 
arrhythmia generation, propagation, and/or maintenance or into the molecular 
determinants of disease risk, prognosis, and progression. In addition, present 
therapeutic strategies for arrhythmia abatement often are ineffective or require 
palliative device therapy after persistent changes in the electrical and 
conduction characteristics of the heart have occurred, changes that appear to 
increase the risk for arrhythmia progression. This article reviews our present 
understanding of the complexity of mechanisms that regulate cardiac membrane 
excitability and cardiac function and explores the role of derangements in these 
mechanisms that interact to induce arrhythmogenic substrates. Approaches are 
recommended for future investigations focused on providing new mechanistic 
insights and therapeutic interventions.