Ynamide coupling reagents have emerged as a significant advancement in peptide synthesis, addressing long-standing issues such as racemization and epimerization. This review details the origin, mechanisms, and applications of ynamide coupling reagents, highlighting their role in greening peptide synthesis. Since the 19th century, peptide chemistry has evolved, but traditional methods are limited by inefficiency and environmental impact. Ynamide coupling reagents, developed over eight years, offer a novel approach for forming amide and ester bonds, effectively suppressing racemization and epimerization. They enable efficient peptide synthesis, including inverse peptide synthesis using unprotected amino acids, and have been applied in solid-phase peptide synthesis, cyclic peptide formation, and thioamide substitution. The reagents are synthesized from inexpensive materials and can be recycled, enhancing their sustainability. Mechanistic studies reveal that ynamide coupling reagents activate carboxylic acids through stable α-acyloxyenamide active esters, leading to efficient aminolysis. Applications include esterification, macrolactonization, and thioamide bond formation, with potential in drug development and protein modification. The development of water-removable ynamide coupling reagents simplifies purification, and their use in peptide synthesis aligns with green chemistry principles. Overall, ynamide coupling reagents represent a promising solution for sustainable and efficient peptide synthesis.Ynamide coupling reagents have emerged as a significant advancement in peptide synthesis, addressing long-standing issues such as racemization and epimerization. This review details the origin, mechanisms, and applications of ynamide coupling reagents, highlighting their role in greening peptide synthesis. Since the 19th century, peptide chemistry has evolved, but traditional methods are limited by inefficiency and environmental impact. Ynamide coupling reagents, developed over eight years, offer a novel approach for forming amide and ester bonds, effectively suppressing racemization and epimerization. They enable efficient peptide synthesis, including inverse peptide synthesis using unprotected amino acids, and have been applied in solid-phase peptide synthesis, cyclic peptide formation, and thioamide substitution. The reagents are synthesized from inexpensive materials and can be recycled, enhancing their sustainability. Mechanistic studies reveal that ynamide coupling reagents activate carboxylic acids through stable α-acyloxyenamide active esters, leading to efficient aminolysis. Applications include esterification, macrolactonization, and thioamide bond formation, with potential in drug development and protein modification. The development of water-removable ynamide coupling reagents simplifies purification, and their use in peptide synthesis aligns with green chemistry principles. Overall, ynamide coupling reagents represent a promising solution for sustainable and efficient peptide synthesis.