Serpins are a superfamily of structurally similar but functionally diverse proteins that inhibit serine proteinases through a unique suicide substrate mechanism. This family has expanded beyond its original classification, with serpins found in metazoa, plantae, and certain viruses. Recent studies reveal that serpins have diverse functions beyond proteinase inhibition, including roles in hormone transport, blood pressure regulation, and host defense. The family is divided into 16 clades and 10 orphan clades based on phylogenetic analysis, with approximately 500 serpins identified. Serpins inhibit serine proteinases of the chymotrypsin family, but some also inhibit cysteine proteinases such as caspase 1 and cathepsins. Some serpins no longer function as proteinase inhibitors but have roles in hormone transport and blood pressure regulation. Serpin structures include a conserved secondary structure with β-sheets and α-helices, and a flexible RSL that facilitates inhibition. Serpins can undergo structural rearrangements that lead to inhibition or non-inhibition of the target proteinase. The inhibitory mechanism involves the RSL inserting into the β-sheet A of the target proteinase, leading to a covalent bond formation and irreversible inhibition. Serpins can also form dimers or higher-order polymers, which may contribute to disease. New serpins, such as ov-serpins and MENT, have been identified with novel functions, including roles in cell survival, chromatin compaction, and neuroprotection. Serpins are involved in various biological processes, including host defense, angiogenesis, and Alzheimer's disease. Plant serpins may also play a role in host defense, and viral serpins are found in certain viruses. Targeted deletions of mouse serpins have shown varied effects on physiology. Serpins are important in development, homeostasis, and host defense, and their study using different biological models is essential for understanding their roles.Serpins are a superfamily of structurally similar but functionally diverse proteins that inhibit serine proteinases through a unique suicide substrate mechanism. This family has expanded beyond its original classification, with serpins found in metazoa, plantae, and certain viruses. Recent studies reveal that serpins have diverse functions beyond proteinase inhibition, including roles in hormone transport, blood pressure regulation, and host defense. The family is divided into 16 clades and 10 orphan clades based on phylogenetic analysis, with approximately 500 serpins identified. Serpins inhibit serine proteinases of the chymotrypsin family, but some also inhibit cysteine proteinases such as caspase 1 and cathepsins. Some serpins no longer function as proteinase inhibitors but have roles in hormone transport and blood pressure regulation. Serpin structures include a conserved secondary structure with β-sheets and α-helices, and a flexible RSL that facilitates inhibition. Serpins can undergo structural rearrangements that lead to inhibition or non-inhibition of the target proteinase. The inhibitory mechanism involves the RSL inserting into the β-sheet A of the target proteinase, leading to a covalent bond formation and irreversible inhibition. Serpins can also form dimers or higher-order polymers, which may contribute to disease. New serpins, such as ov-serpins and MENT, have been identified with novel functions, including roles in cell survival, chromatin compaction, and neuroprotection. Serpins are involved in various biological processes, including host defense, angiogenesis, and Alzheimer's disease. Plant serpins may also play a role in host defense, and viral serpins are found in certain viruses. Targeted deletions of mouse serpins have shown varied effects on physiology. Serpins are important in development, homeostasis, and host defense, and their study using different biological models is essential for understanding their roles.