Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF), and CHF has been shown to be associated with atrial structural remodeling resulting in fibrosis. Atrial interstitial fibrosis has been seen in patients with CHF and in animal models of pacing-induced heart failure. With atrial fibrosis, conduction abnormalities result in increased AF vulnerability. The mechanism of AF associated with CHF is under debate, as both focal and reentrant mechanisms have been observed in animal models of CHF. However, recent studies using frequency-domain analysis have shown that the AF within this model is characterized by discrete, stable, high-frequency areas. The precise signaling processes involved in the development of atrial fibrosis are unknown. Angiotensin appears to play a role, as inhibition of angiotensin-converting enzyme (or angiotensin-receptor blocker) blunts atrial fibrosis in animal models of heart failure and decreases the incidence of AF in patients with heart failure. Transforming growth factor-beta (TGF-beta) also appears to play an important role. Mouse models that overexpress TGF-beta1 have profound atrial fibrosis and AF (with normal ventricles). Heart failure in canine models also produces increases in atrial TGF-beta1 expression, and inhibition of this expression prevents atrial fibrosis and the development of a substrate for AF. Atrial fibrosis appears to play a role in the development of a vulnerable substrate for AF, especially in the setting of CHF.