Single-atom catalysis (SAC) promises to make green technologies economically viable, but the atomic-scale understanding required for further development is difficult to achieve on working catalysts. We will unravel the fine details of single-atom reactivity by studying the catalytic properties of substrate-decoupled 2D metal-organic frameworks (MOFs). These systems mimic the metal-N_x sites reported on the most promising single-atom catalysts, and our methodology provides direct links between atomically defined models and these real systems. We will use graphene as a substrate, whose chemical inertness and structural stability grant us full control over the metal sites within the 2D MOFs: The coordination geometry is defined by the ligand molecules, the chemical properties are determined by the choice of the metal, and the electronic configuration can be adjusted by substrate doping. These three parameters can be varied independently of each other, which will allow us to identify the parameters responsible for the desired functionality and tune the system for optimal performance. Our combined experimental/theoretical approach will provide the atomic-scale understanding needed for the rational design of single-atom catalysts.