Housekeeping enzymes are ubiquitously present in almost all living beings to perform essential metabolic functions for the purpose of survival. These enzymes have been characterized in detail for many years. In recent years, there has been a number of reports indicating that some of these enzymes perform a variety of other functions. In case of many pathogens, certain enzymes play a role to enhance virulence. To perform such a function, enzymes must be located on the surface of pathogens. Although they do not have the typical signal sequence or membrane anchoring mechanisms, they do get secreted and are displayed on the surface, probably by their reassociation. Once on the surface, these enzymes interact with host components, such as fibronectin and plasminogen, or interact directly with the host cells, to trigger signal transduction and thereby enable the pathogens to colonize, persist and invade the host tissue. Therefore, certain housekeeping enzymes may act as putative virulence factors and targets for the development of new strategies to control the infection by using agents that can block their secretion and/or reassociation.