In 1995, Radzicka and Wolfenden reported that the rate enhancement produced by orotidine 5'-phosphate decarboxylase (ODCase) approaches 1017, making this enzyme the most effective pure protein catalyst known in Nature [A. Radzicka, R. Wolfenden, Science 267 (1995) 90-93]. Over the last 12 years, there have been many hypotheses Put forward to explain that impressive effect. In this perspective, we provide a summary of the reaction pathways under consideration for ODCase, highlight the supporting and refuting data, and suggest experiments designed to further test each of the candidate pathways. Published by Elsevier Inc.