The continuum between mutualistic and pathogenic symbioses has been an underlying theme for understanding the evolution of infection and disease in a number of eukaryotic-microbe associations. The ability to monitor and then predict the spread of infectious diseases may depend upon our knowledge and capabilities of anticipating the behavior of virulent pathogens by studying related, benign symbioses. For instance, the ability of a symbiotic species to infect, colonize, and proliferate efficiently in a susceptible host will depend on a number of factors that influence both partners during the infection. Levels of virulence are not only affected by the genetic and phenotypic composite of the symbiont, but also the life history, mode(s) of transmission, and environmental factors that influence colonization, such as antibiotic treatment. Population dynamics of both host and symbiont, including densities, migration, as well as competition between symbionts will also affect infection rates of the pathogen as well as change the evolutionary dynamics between host and symbiont. It is therefore important to be able to compare the evolution of virulence between a wide range of mutualistic and pathogenic systems in order to determine when and where new infections might occur, and what conditions will render the pathogen ineffective. This perspective focuses on several symbiotic models that compare mutualistic associations to pathogenic forms and the questions posed regarding their evolution and radiation. A common theme among these systems is the prevailing concept of how heritable mutations can eventually lead to novel phenotypes and eventually new species.