Multicomponent reactions (MCRs) allow the synthesis of complex molecules in a single step using three or more reactants, offering efficiency and atom economy. This review discusses strategies for improving and inventing MCRs, focusing on the single reactant replacement (SRR) approach. By modifying existing MCRs, researchers can expand their utility in drug discovery and synthetic chemistry. The SRR method involves replacing one reactant with another that mimics its reactivity, enabling the creation of new reaction pathways. Examples include the Passerini reaction, where replacing the carbonyl component with a Lewis acid led to new heterocycles. The Ugi reaction was also reengineered to generate diverse structures. Other MCRs, such as the Fischer indole and Gilman reactions, were modified to enhance their scope and efficiency. The review highlights the importance of retrosynthetic analysis and logical design in developing new MCRs, emphasizing their role in generating complex molecular frameworks for pharmaceutical applications. The SRR approach has proven effective in creating novel reactions, expanding the toolkit for synthetic chemists. The study underscores the value of combining rational design with experimental creativity to advance MCRs in both academic and industrial settings.Multicomponent reactions (MCRs) allow the synthesis of complex molecules in a single step using three or more reactants, offering efficiency and atom economy. This review discusses strategies for improving and inventing MCRs, focusing on the single reactant replacement (SRR) approach. By modifying existing MCRs, researchers can expand their utility in drug discovery and synthetic chemistry. The SRR method involves replacing one reactant with another that mimics its reactivity, enabling the creation of new reaction pathways. Examples include the Passerini reaction, where replacing the carbonyl component with a Lewis acid led to new heterocycles. The Ugi reaction was also reengineered to generate diverse structures. Other MCRs, such as the Fischer indole and Gilman reactions, were modified to enhance their scope and efficiency. The review highlights the importance of retrosynthetic analysis and logical design in developing new MCRs, emphasizing their role in generating complex molecular frameworks for pharmaceutical applications. The SRR approach has proven effective in creating novel reactions, expanding the toolkit for synthetic chemists. The study underscores the value of combining rational design with experimental creativity to advance MCRs in both academic and industrial settings.