Atrial fibrillation (AF) following cardiac surgery is a common complication, which increases incidence of other complications, hospital and healthcare costs. The reported rate of the occurrence of postoperative AF varies with different studies, depending on population profile, type of surgery, arrhythmia definition and detection methods, design of study. Nonetheless, the precise mechanisms of AF related to cardiac surgery are poorly understood. A diverse variety of reasons have been proposed for the pathogenesis of this common cardiac arrhythmia. The aim of this review article is to provide an overview of pathophysiological processes that lead to the development of AF post-cardiac surgery. These processes are closely inter-related but the most important ones that have bearing on drug design include the RAAS, ion channels, connexins, fibrosis and extracellular matrix turnover, inflammation and oxidative stress. The autonomic nervous system and structural remodeling all influence all these pathophysiological processes, which should not be viewed in isolation. Understanding such processes would have major implications for the approach to current pharmaceutical design, to improve our approach to drug management strategies.