Background: Atrial fibrillation is the most common sustained arrhythmia in cardiology. The structural factors leading to atrial fibrillation are well known, but there should be also regarded the functional factors. In 2014, the Task Force published guidelines for atrial fibrillation describing the importance of the vegetative nervous system in creating predisposition to atrial fibrillation although it describes that the mechanism is not completely clear. Furthermore, it is important to understand this mechanism, regarding the increasing number of patients affected by atrial fibrillation without any structural heart diseases. The aim of this work is to understand the physiological background of the predisposition to the appearance and recurrence of atrial fibrillation regarding the role of neural regulatory systems of the heart, especially when no structural heart diseases are present. Therefore, the following is a fundamental analysis of the neural regulation of heart rhythm, including the vegetative nervous system at its medullar and central levels and also the cerebral cortex input in heart regulation. Conclusions: The predisposition to atrial fibrillation regarding the neural regulatory systems of the heart can be pinpointed to three key factors: 1. Central over-activity; 2. Sympathetic efferent overflow towards the heart in rest state; 3. Parasympathetic exhaustion and break-down of the parasymphatetic protective function