The NAD‐dependent histone deacetylase sirtuin (Sirt)1 is implicated in a wide variety of physiological processes, ranging from tumorigenesis to mitochondrial biogenesis to neuronal development. Recent studies indicate that Sirt1 is a critical regulator of both the innate and adaptive immune response in mice and its altered functions are likely involved in autoimmune diseases. Small molecules that modulate Sirt1 functions are potential therapeutic reagents for autoimmune inflammatory diseases. In this review, we highlight the functions of Sirt1 in the immune system focusing on the underlying molecular mechanisms, and the potential of Sirt1 as a therapeutic target for autoimmune diseases.