The sustainable synthesis of relevant scaffolds for their use in the pharmaceutical, agrochemical and material sectors constitutes one of the most urgent challenges that the chemical community needs to overcome. In this context, the development of innovative and more efficient catalytic processes based on fundamental understanding of the underlying reaction mechanisms remains a largely unresolved challenge for academic and industrial chemists. Here, we cover selected examples of computational and experimental knowledge‐driven approaches for the rational design of transition metal catalyzed transformations.