Caspases play a crucial role in apoptotic cell death, acting as a new class of cysteine proteases with over a dozen distinct mammalian family members. These enzymes cleave a limited subset of cellular polypeptides, which are sufficient to account for most cellular and morphological events during apoptosis. Caspases also contribute to escalating the propensity for apoptosis, potentially exacerbating disease pathogenesis. The caspase gene family is divided into two major subfamilies: those related to ICE (caspase-1) and those related to CED-3 in C. elegans. The specificities of caspases can be categorized into three groups based on their substrate preferences. Caspases are synthesized as inactive proenzymes that undergo cleavage at Asp(P1)-X(P1) bonds to become active. The active site of caspases is well defined, with a tight 'socket' for the P1 Asp and a well-conserved catalytic dyad. Caspases recognize a very short tetrapeptide sequence within targeted substrates, with Asp in the P1 position being essential for recognition. Inhibition of caspases has been achieved through the use of electrophiles and irreversible inhibitors, with the latter showing high potency and low reactivity with other biological nucleophiles. Caspases can be activated through three distinct pathways: recruitment-activation, trans-activation, and autoactivation. During apoptosis, only a fraction of the cellular proteome is cleaved by caspases, with about 70 polypeptides identified so far. Caspases are involved in the processing of disease-associated substrates, such as polyglutamine-repeat disorders and Alzheimer's disease, where inappropriate caspase activity can lead to disease exacerbation. Therapeutic interventions targeting caspases have shown promise in treating disorders where insufficient or excessive apoptosis occurs, such as cancer and neurodegeneration, respectively.Caspases play a crucial role in apoptotic cell death, acting as a new class of cysteine proteases with over a dozen distinct mammalian family members. These enzymes cleave a limited subset of cellular polypeptides, which are sufficient to account for most cellular and morphological events during apoptosis. Caspases also contribute to escalating the propensity for apoptosis, potentially exacerbating disease pathogenesis. The caspase gene family is divided into two major subfamilies: those related to ICE (caspase-1) and those related to CED-3 in C. elegans. The specificities of caspases can be categorized into three groups based on their substrate preferences. Caspases are synthesized as inactive proenzymes that undergo cleavage at Asp(P1)-X(P1) bonds to become active. The active site of caspases is well defined, with a tight 'socket' for the P1 Asp and a well-conserved catalytic dyad. Caspases recognize a very short tetrapeptide sequence within targeted substrates, with Asp in the P1 position being essential for recognition. Inhibition of caspases has been achieved through the use of electrophiles and irreversible inhibitors, with the latter showing high potency and low reactivity with other biological nucleophiles. Caspases can be activated through three distinct pathways: recruitment-activation, trans-activation, and autoactivation. During apoptosis, only a fraction of the cellular proteome is cleaved by caspases, with about 70 polypeptides identified so far. Caspases are involved in the processing of disease-associated substrates, such as polyglutamine-repeat disorders and Alzheimer's disease, where inappropriate caspase activity can lead to disease exacerbation. Therapeutic interventions targeting caspases have shown promise in treating disorders where insufficient or excessive apoptosis occurs, such as cancer and neurodegeneration, respectively.