The sirtuins are highly conserved NAD-dependent deacetylases that were shown to regulate lifespan in lower organisms and affect diseases of aging in mammals, such as diabetes, cancer, and inflammation. Most relevant to the amelioration of disease, the SIR2 ortholog SIRT1 has been shown to deacetylate many important transcription factors to exert an overarching influence on numerous metabolic pathways. Here we discuss several diseases of aging for which SIRT1 has been recently shown to confer protection. These findings suggest that manipulating sirtuin activity pharmacologically may be a fruitful area to improve human health.