Multicomponent reactions (MCRs) are one-pot reactions using more than two starting materials, often leading to high atom economy and efficient synthesis. They are widely used in drug discovery due to their ability to generate diverse scaffolds, often through orthogonal functional groups and secondary transformations. MCRs include well-known reactions like Ugi, Passerini, and van Leusen, which produce a variety of scaffolds, including α-acylaminocarboxamides, tetrazoles, and hydantoines. These reactions are valuable for creating libraries of drug-like compounds, often with high scaffold diversity and potential for biological activity. MCRs are particularly useful for generating complex scaffolds, such as bicyclic lactams and polycyclic indole alkaloids, through combinations of different reactions. The chemical space generated by MCRs is vast, with potential for drug discovery, especially in targeting proteins and enzymes. MCRs are also effective in creating scaffolds with specific shapes and functional groups, which are crucial for binding to biological targets. Examples include the synthesis of protease inhibitors, such as α-ketoamides and hydroxymethyl-amides, and the development of kinase inhibitors with flat aromatic structures. MCRs are versatile and can be used to create a wide range of scaffolds, including those with bioisosteric properties, which are important for drug development. The use of MCRs in drug discovery is supported by their ability to generate diverse compounds efficiently, often with high selectivity and activity. The review highlights the importance of MCRs in generating bioactive compounds and their potential in drug discovery, emphasizing the need for further exploration of their biological and chemical properties.Multicomponent reactions (MCRs) are one-pot reactions using more than two starting materials, often leading to high atom economy and efficient synthesis. They are widely used in drug discovery due to their ability to generate diverse scaffolds, often through orthogonal functional groups and secondary transformations. MCRs include well-known reactions like Ugi, Passerini, and van Leusen, which produce a variety of scaffolds, including α-acylaminocarboxamides, tetrazoles, and hydantoines. These reactions are valuable for creating libraries of drug-like compounds, often with high scaffold diversity and potential for biological activity. MCRs are particularly useful for generating complex scaffolds, such as bicyclic lactams and polycyclic indole alkaloids, through combinations of different reactions. The chemical space generated by MCRs is vast, with potential for drug discovery, especially in targeting proteins and enzymes. MCRs are also effective in creating scaffolds with specific shapes and functional groups, which are crucial for binding to biological targets. Examples include the synthesis of protease inhibitors, such as α-ketoamides and hydroxymethyl-amides, and the development of kinase inhibitors with flat aromatic structures. MCRs are versatile and can be used to create a wide range of scaffolds, including those with bioisosteric properties, which are important for drug development. The use of MCRs in drug discovery is supported by their ability to generate diverse compounds efficiently, often with high selectivity and activity. The review highlights the importance of MCRs in generating bioactive compounds and their potential in drug discovery, emphasizing the need for further exploration of their biological and chemical properties.