Atrial fibrillation (AF) constitutes an increasing health problem in the aging population. Animal models reflecting human phenotypes are needed to understand the mechanisms of AF, as well as to test new pharmacological interventions. In recent years, a number of large animal models, primarily pigs, goats, dog and horses have been used in AF research. These animals can to a certain extent recapitulate the human pathophysiological characteristics and serve as valuable tools in investigating new pharmacological interventions for treating AF. This review focuses on anti-arrhythmic investigations in large animals. Initially, spontaneous AF in small and large mammals is discussed. This is followed by a short presentation of frequently used methods for inducing short- and long-term AF. The major focus of the review is on anti-arrhythmic compounds either frequently used in the human clinic (ranolazine, flecainide, vernakalant and amiodarone) or being promising new AF medicine candidates (I_K,Ach, I_SK,Ca and I_K2P blockers).