The article discusses the strategies for innovation in multicomponent reaction (MCR) design, focusing on the application of logic-based approaches, such as the single reactant replacement (SRR) method, to improve known MCRs and design new routes to bioactive structures. MCRs, which involve three or more reactants in a single step, offer advantages in terms of structural complexity, efficiency, and atom economy. The authors highlight the historical development of MCRs, from their early discovery in the mid-19th century to their renewed interest in academic and pharmaceutical research. They describe how their SRR approach, which involves replacing one reactant with a different one that mimics the key reactivity or property necessary for condensation, has led to the discovery of new MCRs and the expansion of the chemical library. The article provides several examples of how this approach has been applied to improve known MCRs, such as the Passerini reaction and Ugi's four-component synthesis, and to design new MCRs for the synthesis of biologically important heterocycles and peptides. The authors conclude by emphasizing the potential of MCRs in combinatorial and diversity-oriented synthesis and the importance of expanding their repertoire for both academic and industrial applications.The article discusses the strategies for innovation in multicomponent reaction (MCR) design, focusing on the application of logic-based approaches, such as the single reactant replacement (SRR) method, to improve known MCRs and design new routes to bioactive structures. MCRs, which involve three or more reactants in a single step, offer advantages in terms of structural complexity, efficiency, and atom economy. The authors highlight the historical development of MCRs, from their early discovery in the mid-19th century to their renewed interest in academic and pharmaceutical research. They describe how their SRR approach, which involves replacing one reactant with a different one that mimics the key reactivity or property necessary for condensation, has led to the discovery of new MCRs and the expansion of the chemical library. The article provides several examples of how this approach has been applied to improve known MCRs, such as the Passerini reaction and Ugi's four-component synthesis, and to design new MCRs for the synthesis of biologically important heterocycles and peptides. The authors conclude by emphasizing the potential of MCRs in combinatorial and diversity-oriented synthesis and the importance of expanding their repertoire for both academic and industrial applications.