There is no doubt that the rational interpretation of the structure-activity relation in catalysis is a crucial task in the quest of engineering the chemical transformation at the molecular. In this respect, multiscale analysis based on structure-dependent microkinetic modelling is acknowledged to be the essential key-tool to achieve a detailed mechanistic understanding of the catalyst functionality. However, the effect of the structure of the catalyst on reactivity and selectivity is at present neglected in state-of-the-art microkinetic modelling. In this talk, I will present the development of a methodology for the analysis of the structure-activity relation in heterogeneous catalysis by hierarchically combining methods at different levels of accuracy in a dual feed-back loop between theory and experiments. This includes the development of both novel experimental tools and first-principles analysis. Selected examples in the context of CH4 activation to syngas will be presented.