In 1995, Radzicka and Wolfenden reported that the rate enhancement produced by orotidine 5'-phosphate decarboxylase (ODCase) approaches 10(17), 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.