Purine nucleoside phosphorylases (PNPs) have been the subject of our scientific interest for a number of years [1]. Despite much progress that has been made in understanding the catalytic mechanism of PNPs, there are still many pieces of the puzzle to be discovered. Recently, we have determined the first crystal structure of PNP from Helicobacter pylori (HpPNP) which is an essential enzyme of its purine salvage pathway [2]. HpPNP seems to posses some unusual features that distinguish it from other PNPs. Moreover, its crucial role in the purine salvage pathway of this serious human pathogen, makes it a very promising drug target [3]. As more and more crystal structures of this enzyme become available, the evidence grows of intricate communication, maybe even allosterically regulated, between the active sites [4]. Perhaps related to this, the number of possible configurations of open and closed active sites in crystal structures is also growing, and HpPNP is displaying even some previously unobserved ones [4]. Various approaches to tackle these open questions, that have crystal structures as a starting point, will be discussed.