The serpins are a superfamily of proteins characterized by a conserved structure and a unique suicide substrate-like inhibitory mechanism. Recent studies have expanded the distribution of serpins within metazoa, plantae, and certain viruses, revealing novel biochemical and biological functions. Serpins primarily inhibit serine proteinases of the chymotrypsin family but also exhibit cross-class inhibition. They adopt a metastable conformation required for their inhibitory activity, involving β-sheets and α-helices. The inhibitory mechanism involves an irreversible suicide substrate pathway, where the reactive site loop (RSL) inserts into β-sheet A, distorting the proteinase and trapping it in an acyl-enzyme intermediate. This mechanism is adaptable to cysteine proteinases, forming a thiol ester-type linkage. Serpins can form dimers and higher-order oligomers, which can lead to disease through aggregate formation. New serpins, such as ov-serpins and neuroserpin, have been identified with diverse functions, including cell survival, barrier function, and host defense. Plant serpins may play roles in host defense, while viral serpins are found in various genera of poxviruses and gamaherpaviruses. The study of serpin function across different biological platforms, such as nematodes and fruit flies, aims to uncover their roles in development, homeostasis, and host defense.The serpins are a superfamily of proteins characterized by a conserved structure and a unique suicide substrate-like inhibitory mechanism. Recent studies have expanded the distribution of serpins within metazoa, plantae, and certain viruses, revealing novel biochemical and biological functions. Serpins primarily inhibit serine proteinases of the chymotrypsin family but also exhibit cross-class inhibition. They adopt a metastable conformation required for their inhibitory activity, involving β-sheets and α-helices. The inhibitory mechanism involves an irreversible suicide substrate pathway, where the reactive site loop (RSL) inserts into β-sheet A, distorting the proteinase and trapping it in an acyl-enzyme intermediate. This mechanism is adaptable to cysteine proteinases, forming a thiol ester-type linkage. Serpins can form dimers and higher-order oligomers, which can lead to disease through aggregate formation. New serpins, such as ov-serpins and neuroserpin, have been identified with diverse functions, including cell survival, barrier function, and host defense. Plant serpins may play roles in host defense, while viral serpins are found in various genera of poxviruses and gamaherpaviruses. The study of serpin function across different biological platforms, such as nematodes and fruit flies, aims to uncover their roles in development, homeostasis, and host defense.