Multicomponent reactions (MCRs) are one-pot reactions that utilize more than two starting materials to form a single product, incorporating most of the atoms from the starting materials. MCRs are characterized by their atom economy, efficiency, convergence, and high bond-forming index. They are useful alternatives to sequential multistep synthesis and have been widely used in drug discovery due to their ability to produce a diverse range of scaffolds in a single reaction. The Ugi, Passerini, van Leusen, Strecker, Hantzsch, and Biginelli reactions are notable examples of MCRs. MCRs can be further modified with orthogonal functional groups to enhance scaffold diversity, leading to a vast array of novel scaffolds suitable for combinatorial and medicinal chemistry. The chemical space of MCRs is vast, encompassing a large number of possible molecules, making it a valuable resource for drug discovery. The 3D shape, H-bond donor and acceptor distribution, and charge distribution of MCR-derived compounds are crucial for their biological activity and drug-like properties. MCRs have been successfully used to synthesize various scaffolds, including bicyclic lactams, spiroheterocycles, and macrocycles, which are often challenging to access through other synthetic methods. MCRs have been applied to target classes such as proteases, kinases, and phosphatases. For proteases, MCRs have been used to synthesize diverse protease inhibitors, including α-ketoamide and hydroxymethyl-amide-based compounds. Kinase inhibitors, particularly those targeting p38 kinase, have also been synthesized using MCRs, with some showing promising clinical potential. Phosphatase inhibitors, such as glucose-6-phosphate translocase inhibitors, have been developed using MCRs, demonstrating the versatility of these reactions in drug discovery. Overall, MCRs offer a powerful tool for the rapid and efficient synthesis of a wide range of scaffolds, making them an essential component in the toolkit of synthetic chemists and medicinal researchers.Multicomponent reactions (MCRs) are one-pot reactions that utilize more than two starting materials to form a single product, incorporating most of the atoms from the starting materials. MCRs are characterized by their atom economy, efficiency, convergence, and high bond-forming index. They are useful alternatives to sequential multistep synthesis and have been widely used in drug discovery due to their ability to produce a diverse range of scaffolds in a single reaction. The Ugi, Passerini, van Leusen, Strecker, Hantzsch, and Biginelli reactions are notable examples of MCRs. MCRs can be further modified with orthogonal functional groups to enhance scaffold diversity, leading to a vast array of novel scaffolds suitable for combinatorial and medicinal chemistry. The chemical space of MCRs is vast, encompassing a large number of possible molecules, making it a valuable resource for drug discovery. The 3D shape, H-bond donor and acceptor distribution, and charge distribution of MCR-derived compounds are crucial for their biological activity and drug-like properties. MCRs have been successfully used to synthesize various scaffolds, including bicyclic lactams, spiroheterocycles, and macrocycles, which are often challenging to access through other synthetic methods. MCRs have been applied to target classes such as proteases, kinases, and phosphatases. For proteases, MCRs have been used to synthesize diverse protease inhibitors, including α-ketoamide and hydroxymethyl-amide-based compounds. Kinase inhibitors, particularly those targeting p38 kinase, have also been synthesized using MCRs, with some showing promising clinical potential. Phosphatase inhibitors, such as glucose-6-phosphate translocase inhibitors, have been developed using MCRs, demonstrating the versatility of these reactions in drug discovery. Overall, MCRs offer a powerful tool for the rapid and efficient synthesis of a wide range of scaffolds, making them an essential component in the toolkit of synthetic chemists and medicinal researchers.