Single-atom catalysts (SACs) have recently attracted interest in the fields of heterogeneous catalysis and electrocatalysis due to the enhancement in intrinsic activity and selectivity through optimized exposure of the active sites. Synthesis of SACs and research into their behavior have helped to elucidate the kinetics and thermodynamics of several key catalytic reactions. However, understanding the interactions between the metal single-atom active sites and the support matrix represents a notable challenge facing the development of atomically dispersed catalysts. Such interactions are essential in optimizing the reaction kinetics and maximizing the catalytic performance. This review explores the current state of the art in single-atom catalysis and critically analyzes the current understanding of metal-support interactions. Finally, we discuss the current challenges and future opportunities for development in the field.