Glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2. 1.12) has classically been regarded as an ubiquitous enzyme of little importance beyond its role in glycolysis. Indeed, the most frequent reference to GAPDH in recent scientific literature is as the “housekeeping” gene used to standardize Northern blots. A careful examination of the literature of the last 25 years, however, reveals a number of novel actions of GAPDH beyond a role in glycolysis. A review of these novel functions of GAPDH is beyond the scope of this chapter, and the reader is referred to a number of recent thorough reviews by Michael Sirover for further details (1,2). Of the novel functions identified for GAPDH, one of the most intriguing is as an integral part of one or more apoptotic cascades. Here, we will briefly outline the evidence for GAPDH not only playing a role in the initiation of apoptosis, but also being a target of a number of known antiapoptotic compounds. A more in-depth discussion of the role of GAPDH in apoptosis is provided in our recent review article (3).