High density lipoprotein (HDL) cholesterol has beneficial effects beyond its atheroprotective function in reverse cholesterol transport, including cardioprotection against ischemia reperfusion (IR) injuries. Two major constituents of HDL, namely the structural protein apolipoprotein AI (apoAI) and the sphingolipid sphingosine-1-phosphate (S1P) appear to contribute to this cardioprotective effect via the activation of intrinsic prosurvival signaling pathways that still remain to be clarified.   Recently, a powerful prosurvival signaling pathway, termed the survivor activating factor enhancement (SAFE) pathway, which involves the activation of signal transducer and activator of transcription 3 (STAT3) and tumor necrosis factor α (TNF), has been shown to protect against ischemia-reperfusion injuries. The present review summarizes the evidence for the roles of HDL and S1P in cardioprotection and discusses the signaling pathways that have been implicated. It thus provides support for our contention that S1P should be considered in potential formulations of reconstituted HDL (reHDL) that may be tested for cardioprotection against coronary artery disease via the activation of the SAFE pathway.