Traditionally, atrial fibrillation (AF) is attributed to multiple re-entry circuits due to conduction and refractoriness abnormalities. However lines of evidence point to the importance of focal mechanisms and of abnormalities in intracellular Ca handling as missing links in AF-initiating focal activity and in perpetuation by re-entry. The sustained atrial tachycardia during AF leads to electrical and structural remodeling that promotes the persistence and the progression of the arrhythmia. In AF patients, atrial tachycardia and heart disease-based remodeling coexist, resulting in highly complex changes of atrial function involving re-entry and Ca2+ – related triggered activity-based focal sources. Recent evidence suggests that phosphorylation of ryanodine receptor channels (RyR2) at Ser2814 is increased in AF patients leading to RyR2 leakiness which is well-established contributors to cardiac dysfunction and arrhythmogenesis. In addition, reduced inhibition of Serca2a by CaMKII hyperphosphorylated (less active) phospholamban helps to maintain a normal sarcoplasmic reticulum (SR) Ca-load, but this supports the incidence of spontaneous diastoclic Ca-release events (sparks) and Ca waves through leaky RyR2 channels. Results using a knock-in mouse model in which the CaMKII phosphorylation site on RyR2 had been genetically ablated by substitution of serine by non-phosphorylable alanine (S2814A) demonstrated that inhibition of Ser2814 phosphorylation on RyR2 prevents induction of pacing-induced AF in S2814A mice. Cellular findings showed that inhibition of CaMKII reduces RyR2 open probability and prevents diastolic SR Ca leak through RyR2. These data suggest that enhanced phosphorylation of RyR2 is a critical downstream target of activated CaMKII signaling in fibrillating atria. Thus, Ca- and CaMKII-related triggered activity may be a novel focal mechanism in the progression and maintenance of AF.