This study investigates the role of Sir2 homolog (SIRT1) in normal cells and developmental processes. SIRT1 is a mammalian homolog of the *Saccharomyces cerevisiae* chromatin silencing factor Sir2, and it has been implicated in deacetylating the p53 tumor suppressor protein to dampen apoptotic and cellular senescence pathways. To understand SIRT1 function, researchers generated mice with either a mutant SIRT1 protein lacking part of the catalytic domain or no detectable SIRT1 protein at all. Both types of SIRT1 mutant mice exhibited similar phenotypes, including small size, developmental defects in the retina and heart, and frequent postnatal mortality. SIRT1-deficient cells showed increased p53 hyperacetylation after DNA damage and enhanced ionizing radiation-induced thymocyte apoptosis. However, p53 hyperacetylation did not lead to increased p21 protein induction or DNA damage sensitivity in SIRT1-deficient embryonic fibroblasts. These findings provide direct evidence that endogenous SIRT1 regulates p53 acetylation and p53-dependent apoptosis, and that SIRT1 is essential for specific developmental processes. The study also highlights the role of SIRT1 in eye morphogenesis and retinal development, and suggests that SIRT1 may modulate p53 responses and other processes in adult tissues.This study investigates the role of Sir2 homolog (SIRT1) in normal cells and developmental processes. SIRT1 is a mammalian homolog of the *Saccharomyces cerevisiae* chromatin silencing factor Sir2, and it has been implicated in deacetylating the p53 tumor suppressor protein to dampen apoptotic and cellular senescence pathways. To understand SIRT1 function, researchers generated mice with either a mutant SIRT1 protein lacking part of the catalytic domain or no detectable SIRT1 protein at all. Both types of SIRT1 mutant mice exhibited similar phenotypes, including small size, developmental defects in the retina and heart, and frequent postnatal mortality. SIRT1-deficient cells showed increased p53 hyperacetylation after DNA damage and enhanced ionizing radiation-induced thymocyte apoptosis. However, p53 hyperacetylation did not lead to increased p21 protein induction or DNA damage sensitivity in SIRT1-deficient embryonic fibroblasts. These findings provide direct evidence that endogenous SIRT1 regulates p53 acetylation and p53-dependent apoptosis, and that SIRT1 is essential for specific developmental processes. The study also highlights the role of SIRT1 in eye morphogenesis and retinal development, and suggests that SIRT1 may modulate p53 responses and other processes in adult tissues.