Recent discoveries of AMPK activators point to the large number of therapeutic candidates that can be transformed to successful designs of novel drugs. AMPK is a universal energy sensor and influences almost all physiological processes in the cells. Thus, regulation of the cellular energy metabolism can be achieved in selective tissues via the artificial activation of AMPK by small molecules. Recently, special attention has been given to direct activators of AMPK that are regulated by several nonspecific upstream factors. The direct activation of AMPK, by definition, should lead to more specific biological activities and as a result minimize possible side effects.