The enzymatic role of the pro-inflammatory protein COX-2 in regulating a wide variety of cellular functions is well established and undisputed. We posit that in addition to its canonical enzymatic role, the COX-2 protein itself plays an enzymatic activity independent roles in regulating cell function. Specifically we focus on identifying a role for COX-2 limited proteolysis in cell proliferation, and cellular pathways that lead to elimination of the COX-2 protein. Understanding the role of COX-2 fragments in regulating cell proliferation is meritorious as it has the potential to lead to the development of novel means of treating diseases associated with sustained expression of COX-2 by either specific protease inhibitors or small peptides that directly target their specific cleavage sites in this protein.