The members of the Sir2 family, or Sirtuins, have garnered considerable attention because of their key roles as metabolic sensors and mediators of cell survival under stress. Sirtuins may play roles in myriad human pathologies such as cancer, neurological diseases, malaria, leishmaniasis and hormone-related disorders. They are present from prokaryotes to humans and show a high degree of functional diversification that has led to two different enzymatic activities, a wide range of substrates and a highly diversified pattern of cellular localization. Throughout chromatin evolution, Sirtuins have maintained an intimate functional relationship in regulating its structure and function via their targeting of histones, particularly H4K16Ac, as well as other non-histone chromatin proteins. This link permitted fast communication from metabolic fluctuations to chromatin allowing efficient adaptation to environmental stimuli. Therefore, understanding the common path of Sirtuins and chromatin development over the course of evolution might be important for understanding not only the remarkable diversity of functions of these proteins in mammals, but also the path followed by chromatin evolution. Herein is provided an overview of current knowledge of Sirtuin function, from bacteria to humans, including a discussion on its implications for chromatin dynamics, organization and integrity.