Sirtuin (the mammalian homolog of silent information regulation 2 of yeast Saccharomyces cerevisiae) 1 (SIRT1), a NAD-dependent histone deacetylase, has emerged as a critical regulator in response to oxidative stress. Through antagonism of oxidative stress-induced cell injury and through the maintenance of metabolic homeostasis in the body, SIRT1 can block vascular system injury. SIRT1 targets multiple cellular proteins, such as peroxisome proliferator-activated receptor-γ and its coactivator-1α, forkhead transcriptional factors, AMP-activated protein kinase, NF-κB and protein tyrosine phosphatase to modulate intricate cellular pathways of multiple diseases. In the cardiovascular system, activation of SIRT1 can not only protect against oxidative stress at the cellular level, but can also offer increased survival at the systemic level to limit coronary heart disease and cerebrovascular disease. Future knowledge regarding SIRT1 and its novel pathways will open new directions for the treatment of cardiovascular disease as well as offer the potential to limit disability from several related disorders.