The sirtuin family, a group of NAD+-dependent enzymes, has emerged as crucial regulators of cellular fate and mammalian physiology. Initially identified in yeast as silencing factors, sirtuins have been linked to a wide range of activities, including cellular stress resistance, genomic stability, tumorigenesis, and energy metabolism. Recent progress has revealed that sirtuins play significant roles in various age-related diseases and may regulate lifespan. The review highlights the diverse physiological roles of sirtuins, such as their involvement in DNA repair, cell fate regulation, metabolic control, and age-related diseases. Despite the growing understanding of sirtuin functions, many questions remain, particularly regarding the regulation of sirtuin activity under normal and stress conditions, as well as during aging. The discovery of interacting proteins that modulate sirtuin activity suggests that similar mechanisms may exist for other sirtuin family members. Pharmacological manipulation of sirtuin activity, initially using resveratrol, has expanded to include newer agents with greater specificity, some of which are already in human clinical trials. The evolving connections between acetylation, energetics, and gene expression highlight the complex and multifaceted role of sirtuins in cellular and organismal processes.The sirtuin family, a group of NAD+-dependent enzymes, has emerged as crucial regulators of cellular fate and mammalian physiology. Initially identified in yeast as silencing factors, sirtuins have been linked to a wide range of activities, including cellular stress resistance, genomic stability, tumorigenesis, and energy metabolism. Recent progress has revealed that sirtuins play significant roles in various age-related diseases and may regulate lifespan. The review highlights the diverse physiological roles of sirtuins, such as their involvement in DNA repair, cell fate regulation, metabolic control, and age-related diseases. Despite the growing understanding of sirtuin functions, many questions remain, particularly regarding the regulation of sirtuin activity under normal and stress conditions, as well as during aging. The discovery of interacting proteins that modulate sirtuin activity suggests that similar mechanisms may exist for other sirtuin family members. Pharmacological manipulation of sirtuin activity, initially using resveratrol, has expanded to include newer agents with greater specificity, some of which are already in human clinical trials. The evolving connections between acetylation, energetics, and gene expression highlight the complex and multifaceted role of sirtuins in cellular and organismal processes.