Healthy cardiac conduction and function relies on the coordinated electrical activity of distinct populations of cardiomyocytes. Disruption of cell-cell conduction results in cardiac arrhythmias and cardiomyopathies, a leading cause of morbidity and mortality worldwide. We investigated the mechanisms of arrhythmia formation from several angles. Recent genetic studies have highlighted a major heritable component and identified numerous loci associated with risk of arrhythmias such as atrial fibrillation, including transcription factor genes TBX5 and GATA4. We defined a novel calcium-dependent mechanism of atrial fibrillation following transcription factor Tbx5 insufficiency. We then examined the coregulatory relationship between Tbx5 and Gata4 in maintaining atrial rhythm and found that AF pathophysiology caused by Tbx5 haploinsufficiency, including was rescued by Gata4 haploinsufficiency. In addition to transcription factors, many other proteins, particularly those important for electrical and physical coupling between cells can regulate cardiac conduction. We show inducible loss of the intercalated disc protein ZO-1 in cardiomyocytes of adult mice impedes AV node conduction and modestly affects ejection fraction.