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The Yamaguchi reagent, based on 2,4,6-trichlorobenzoyl chloride (TCBC) and 4-dimethylaminopyridine (DMAP), is an efficient tool for conducting the intermolecular (esterification) reaction between an acid and an alcohol in the presence of a suitable base (Et 3 N or i Pr 2 NEt) and solvent (THF, DCM, or toluene). The Yamaguchi protocol is renowned for its ability to efficiently produce a diverse array of functionalized esters, promoting high yields, regioselectivity, and easy handling under mild conditions with short reaction times. Here, the recent utilization of the Yamaguchi reagent was reviewed in the synthesis of various natural products such as macrolides, terpenoids, polyketides, peptides, and metabolites., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Munir, Zahoor, Anjum, Mansha, Irfan, Chaudhry, Irfan, Kotwica-Mojzych, Glowacka and Mojzych.)