This comprehensive review, covering the period from 2021 to 2023, explores the multifaceted chemical and pharmacological potential of coumarins, emphasizing their significance as versatile natural derivatives in medicinal chemistry. The synthesis and functionalization of coumarins have advanced with innovative strategies, enabling the incorporation of diverse functional fragments or the construction of supplementary cyclic architectures, thereby enhancing the biological and physico-chemical properties of the compounds obtained. The unique chemical structure of coumarins facilitates binding to various targets through hydrophobic interactions, pi-stacking, hydrogen bonding, and dipole-dipole interactions, making them promising applications in numerous fields of medicinal chemistry, such as neurodegenerative diseases, cancer, and inflammation. Coumarins represent one of the most privileged scaffolds in natural products and bioactive molecules. Their diverse array of biological characteristics, including antioxidant, anticonvulsant, antitumor, anti-inflammatory, and antimicrobial activities, have made them appealing to medicinal chemists. Several coumarin derivatives have been approved by the FDA for clinical usage, such as anticoagulant drugs like warfarin, acenocoumarol, dicoumarol, and phenprocoumon, as well as trioxsalen for treating vitiligo and esculin for hemorrhoids. The ready availability and low price of starting materials for synthesizing coumarins have enabled the development of a wide range of methodologies. The distinct reactivities associated with the C-3 and C-4 positions of the coumarin system have paved the way for selective modifications, introducing pertinent functional groups and facilitating the construction of cyclic systems. Classical methods for the synthesis of coumarins include Knoevenagel, Perkin, Pechmann, Wittig, Claisen, and Reformatsky reactions. The review covers the synthesis of 3-substituted, 4-substituted, and decorated or bicyclic coumarins, including innovative strategies such as green syntheses, photo- and metal-catalyzed reactions, and multi-component approaches. Examples include the synthesis of 3-alkyl, 3-heteroaryl, 3-acetyl, and 3-nitro coumarins, as well as 4-substituted coumarins through C-H functionalizations and Pechmann condensations. The reactivity of coumarins, particularly at the C-3 and C-4 positions, has been extensively studied. This includes the introduction of alkyl, silyl, CF3, CHF3, and OCH2F groups, as well as the synthesis of 3-acyl, 3-aryl, 3-carboxy, 3-nitro, 3-cyano, 3-acetamido, and N-methoxy-3-carboxamide coumarins. Transition-metal-catalyzed annulation reactions areThis comprehensive review, covering the period from 2021 to 2023, explores the multifaceted chemical and pharmacological potential of coumarins, emphasizing their significance as versatile natural derivatives in medicinal chemistry. The synthesis and functionalization of coumarins have advanced with innovative strategies, enabling the incorporation of diverse functional fragments or the construction of supplementary cyclic architectures, thereby enhancing the biological and physico-chemical properties of the compounds obtained. The unique chemical structure of coumarins facilitates binding to various targets through hydrophobic interactions, pi-stacking, hydrogen bonding, and dipole-dipole interactions, making them promising applications in numerous fields of medicinal chemistry, such as neurodegenerative diseases, cancer, and inflammation. Coumarins represent one of the most privileged scaffolds in natural products and bioactive molecules. Their diverse array of biological characteristics, including antioxidant, anticonvulsant, antitumor, anti-inflammatory, and antimicrobial activities, have made them appealing to medicinal chemists. Several coumarin derivatives have been approved by the FDA for clinical usage, such as anticoagulant drugs like warfarin, acenocoumarol, dicoumarol, and phenprocoumon, as well as trioxsalen for treating vitiligo and esculin for hemorrhoids. The ready availability and low price of starting materials for synthesizing coumarins have enabled the development of a wide range of methodologies. The distinct reactivities associated with the C-3 and C-4 positions of the coumarin system have paved the way for selective modifications, introducing pertinent functional groups and facilitating the construction of cyclic systems. Classical methods for the synthesis of coumarins include Knoevenagel, Perkin, Pechmann, Wittig, Claisen, and Reformatsky reactions. The review covers the synthesis of 3-substituted, 4-substituted, and decorated or bicyclic coumarins, including innovative strategies such as green syntheses, photo- and metal-catalyzed reactions, and multi-component approaches. Examples include the synthesis of 3-alkyl, 3-heteroaryl, 3-acetyl, and 3-nitro coumarins, as well as 4-substituted coumarins through C-H functionalizations and Pechmann condensations. The reactivity of coumarins, particularly at the C-3 and C-4 positions, has been extensively studied. This includes the introduction of alkyl, silyl, CF3, CHF3, and OCH2F groups, as well as the synthesis of 3-acyl, 3-aryl, 3-carboxy, 3-nitro, 3-cyano, 3-acetamido, and N-methoxy-3-carboxamide coumarins. Transition-metal-catalyzed annulation reactions are