T-cell death is a fundamental process that is intricately regulated at multiple phases during T-cell differentiation, tolerance induction and the decline of the immune response. Caspase 3 is a crucial molecule regulating both mitochondrial and death receptor apoptotic pathways and therefore we were interested in examining the role of caspase 3 in T cells. Using P14 and H-Y CD8+ TCR-transgenic models, our analysis has shown that caspase 3 is not required for thymic negative selection. In addition, caspase 3 does not play a prominent role in the contraction phase following acute viral infection, nor clonal deletion of CD8+ T cells under tolerizing conditions. Surprisingly, our studies demonstrate that caspase 3 was not required for the induction of CD8+ T-cell anergy in vivo, contrary to published reports using CD4+ T cells. Therefore, these results demonstrate that caspase 3 is not essential in CD8+ T cells for multiple forms of thymic or peripheral tolerance, nor the contraction phase after an acute anti-viral response.