This review provides an extensive update on the caspase substrates involved in apoptotic cell death, highlighting the significant increase in the number of identified substrates from 65 in 1998 to over 280 today. The authors discuss the functional consequences of caspase-mediated cleavage, which can either inactivate or activate proteins, often leading to gain-of-function effects. Key morphological alterations in apoptosis, such as DNA fragmentation, chromatin condensation, and cytoskeletal reorganization, are regulated by specific caspase substrates. The review also explores the role of caspases in signal transduction, where they can either inhibit or activate proteins, and their involvement in disease progression, particularly in neurodegenerative disorders and autoimmune diseases. Additionally, the authors discuss the limited and selective activation of caspases during terminal differentiation and hematopoiesis, suggesting a dual role of caspases in both cell death and non-apoptotic processes. The review emphasizes the need for further research to understand the mechanisms behind the selective cleavage of specific substrates and the regulatory mechanisms that control caspase activity in different cellular contexts.This review provides an extensive update on the caspase substrates involved in apoptotic cell death, highlighting the significant increase in the number of identified substrates from 65 in 1998 to over 280 today. The authors discuss the functional consequences of caspase-mediated cleavage, which can either inactivate or activate proteins, often leading to gain-of-function effects. Key morphological alterations in apoptosis, such as DNA fragmentation, chromatin condensation, and cytoskeletal reorganization, are regulated by specific caspase substrates. The review also explores the role of caspases in signal transduction, where they can either inhibit or activate proteins, and their involvement in disease progression, particularly in neurodegenerative disorders and autoimmune diseases. Additionally, the authors discuss the limited and selective activation of caspases during terminal differentiation and hematopoiesis, suggesting a dual role of caspases in both cell death and non-apoptotic processes. The review emphasizes the need for further research to understand the mechanisms behind the selective cleavage of specific substrates and the regulatory mechanisms that control caspase activity in different cellular contexts.