This paper addresses the potential for using virulence factor–activity relationships (VFAR) to discover and detect emerging waterborne pathogens. Emerging pathogens present two challenges to drinking water safety. The first is to improve the predictive value of tests for novel organisms that have recently been identified as emerging waterborne health threats, but are not yet well characterized. There are potential applications for VFAR in meeting this challenge, most notably to distinguish pathogens from closely related nonpathogenic organisms that may also be present in water samples. The second challenge is to prospectively identify new organisms that are not yet known to be health risks to humans, but have the potential of becoming so. This goal is more ambitious. Many microbial virulence factors have multiple functions, some of which are innocuous. Moreover, dedicated virulence factors can be found in pathogens that infect non-human hosts, but pose no threat to humans. These issues complicate the near-term use of VFAR as a first line indicator of pathogenicity. However, our understanding of microbial pathogenesis continues to expand exponentially. As known virulence factors increase in number, so too does the feasibility of a prognostic VFAR strategy.