The successful zebrafish developmental model has now expanded to being used as a model for the analysis of host-pathogen interactions during infectious disease. Numerous pathogens have been demonstrated to infect zebrafish and new mechanisms of virulence, as well as host defense have been uncovered using this new model. In this review we summarize the literature on how the zebrafish infectious disease model is being used to decipher virulence mechanisms used by various pathogens and the host defense mechanisms initiated to combat infection.