The Queen's Gambit is an opening move in chess that provides a variety of aggressive options to the player electing it. This report represents a similar gambit (the 'Sicilian Gambit') on the part of a group of basic and clinical investigators who met in Taormina, Sicily, to consider the classification of antiarrhythmic drugs. Paramount to their considerations were (1) dissatisfaction with the options offered by existing classification systems for inspiring and directing research, development and therapy, (2) the disarray in the field of antiarrhythmic drug development and testing in this post-CAST era, and (3) the desire to provide an operational framework for consideration of antiarrhythmic drugs that will both encourage advancement and have the plasticity to grow as a result of the advances that occur. The multifaceted approach suggested is, like the title of the manuscript, a gambit. It is an opening rather than a compendium, and is intended to challenge thought and investigation rather than to resolve issues. The manuscript incorporates first, a discussion of the shortcomings of the present system for drug classification; second, a review of the molecular targets on which drugs act (including channels and receptors); third, a consideration of the mechanisms responsible for arrhythmias, including the identification of 'vulnerable parameters' that might be most accessible to drug effect; and finally, clinical considerations with respect to antiarrhythmic drugs. Information relating to the various levels of information is correlated across categories (i.e., clinical arrhythmias, cellular mechanisms and molecular targets), and a 'spread sheet' approach to antiarrhythmic action is presented that considers each drug as a unit, with similarities to and dissimilarities from other drugs being highlighted. A complete reference list for this work would require as many pages as the text itself. For this reason, referencing is selective and incomplete. It is designed, in fact, to provide sufficient background information to give the interested reader a starting frame of reference, rather than to recognize the complete body of literature that is the basis for this paper.