In the 15 years since the first publication on ischemic preconditioning (PC), our knowledge of this phenomenon has increased exponentially. While the original studies described the early phase of ischemic PC, we now know that a second or late phase of ischemic PC also exists. In particular, the late phase of PC is triggered by factors such as adenosine, opioids, radicals, and nitric oxide. These factors in turn initiate a molecular chain reaction, which includes activation of serine/threonine kinases, tyrosine kinases, and mitogen-activated protein kinases. Subsequently, this cascade of reactions modulates a plethora of cardioprotective proteins including heat shock proteins, KATP channels, nitric oxide synthase, cyclooxygenase-2, and antioxidants. However, despite this phenomenal amount of information, the construction of a unifying hypothesis describing the signaling mechanism of late PC has proved challenging. The purpose of this article, therefore, is to review the current literature and hypothesis regarding the signaling system in the late phase of ischemic PC, to tackle areas of controversy within this model, and to address potential future directions of investigation that will hopefully promote the generation of a unifying paradigm.