AbstractThe sirtuin family of class III histone deacetylases has been extensively implicated in modulating a myriad of cellular processes, including energy metabolism, stress response, cell/tissue survival and malignancy. Recent studies have also identified multifaceted roles for Sirt1 and Sirt2 in the regulation of autophagy. Sirt1 could influence autophagy directly via its deacetylation of key components of the autophagy induction network, such as the products of autophagy genes (Atg) 5, 7, and 8. Nucleus‐localized Sirt1 is also known to induce the expression of autophagy pathway components through the activation of FoxO transcription factor family members. The perception of a linear Sirt1‐FoxO axis in autophagy induction is complicated by recent findings that acetylated FoxO1 could bind to Atg7 in the cytoplasm and affect autophagy directly. This occurs with prolonged stress signaling, with FoxO1's continuous dissociation from cytoplasmic Sirt2 and its consequential hyperacetylation. FoxO‐mediated nuclear transcription may induce/enhance autophagy in ways that are different compared to cytoplasmic FoxO, thereby leading to contrasting (cell survival versus cell death) outcomes. FoxO and Sirt1 are both subjected to regulation by stress signaling (e.g., through the c‐Jun N‐terminal kinases (JNK)) in the context of autophagy induction, which are also critical in determining between cell survival and death in a context‐dependent manner. We discussed here the emerging molecular intricacies of sirtuins' connections with autophagy. A good understanding of these connections would serve to consolidate a framework of mechanisms underlying Sirt1's protective effects in multiple physiological systems. J. Cell. Physiol. 228: 2262–2270, 2013. © 2013 Wiley Periodicals, Inc.