Virulence factor activity relationships (VFAR) is a predictive approach proposed by the National Research Council's Committee on Drinking Water Contaminants (Washington, D.C.) to classify and rank waterborne pathogens. It is based on the presumption that health threats of waterborne pathogens can be predicted from descriptors at different levels of cellular organization. This paper summarizes challenges that need to be addressed while developing VFAR, with a focus on genomics, such as genomic variability among related pathogens and the need to incorporate genetic descriptors for persistence and host susceptibility. Three key components of VFAR development and validation are also presented, including (1) compilation of a comprehensive VFAR database, (2) development of predictive mathematical models relating descriptors to health effects and other microbial responses, and (3) high-throughput molecular monitoring of drinking water supplies and sources. Bayesian approach and on-chip polymerase chain reaction are discussed as examples of mathematical models and molecular monitoring.