This study investigates the essential role of caspase 3 (CPP32) in apoptosis using *CPP32ex3−/−* mice, embryonic stem (ES) cells, and mouse embryonic fibroblasts (MEFs). *CPP32ex3−/−* mice exhibit reduced viability and neurological defects, consistent with previous reports. Inactivation of *CPP32* significantly reduces apoptosis in various contexts, including activation-induced cell death (AICD) of peripheral T cells and chemotherapy-induced apoptosis of oncogenically transformed MEFs. The requirement for CPP32 is stimulus-dependent: In ES cells, CPP32 is necessary for efficient apoptosis following UV-irradiation but not γ-irradiation. Conversely, in oncogenically transformed MEFs, TNFα treatment induces normal apoptosis in *CPP32−/−* cells but not in wild-type cells. Additionally, in some cell types, CPP32 is required for chromatin condensation and DNA degradation but not other apoptotic events. These findings indicate that CPP32 is a critical component of apoptotic events that is system- and stimulus-dependent, suggesting that inhibitors targeting CPP32 may disrupt specific forms of cell death.This study investigates the essential role of caspase 3 (CPP32) in apoptosis using *CPP32ex3−/−* mice, embryonic stem (ES) cells, and mouse embryonic fibroblasts (MEFs). *CPP32ex3−/−* mice exhibit reduced viability and neurological defects, consistent with previous reports. Inactivation of *CPP32* significantly reduces apoptosis in various contexts, including activation-induced cell death (AICD) of peripheral T cells and chemotherapy-induced apoptosis of oncogenically transformed MEFs. The requirement for CPP32 is stimulus-dependent: In ES cells, CPP32 is necessary for efficient apoptosis following UV-irradiation but not γ-irradiation. Conversely, in oncogenically transformed MEFs, TNFα treatment induces normal apoptosis in *CPP32−/−* cells but not in wild-type cells. Additionally, in some cell types, CPP32 is required for chromatin condensation and DNA degradation but not other apoptotic events. These findings indicate that CPP32 is a critical component of apoptotic events that is system- and stimulus-dependent, suggesting that inhibitors targeting CPP32 may disrupt specific forms of cell death.