Streptococcal pathogens continue to evade concerted efforts to determine clear-cut virulence mechanisms, although numerous genes have been implicated in pathogenesis. A single species can infect a diversity of tissues, suggesting the expression of specific virulence factors based on the local tissue environment or stage of infection. In an effort to identify the interactions that occur between the host and pathogen that lead to activation of virulence mechanisms and contribute to specific streptococcal disease states, we have developed a unique animal model, the zebrafish (Danio rerio), to characterize specific virulence mechanisms utilized within various tissues in vivo. We are using this model host to study infection by two streptococcal species that represent two forms of streptococcal disease: a natural pathogen of fish and humans, Streptococcus iniae and a human-specific pathogen, Streptococcus pyogenes. S. iniae primarily causes a fatal systemic disease in the zebrafish following intra-muscular injection, with similar pathologies to that seen in human infections caused by Streptococcus agalactiae and S. pneumoniae. While the fatal infection by S. pyogenes causes a locally spreading necrotic disease confined to the muscle with pathology similar to what is observed in a human infection of necrotizing fasciitis. By studying pathogens that are virulent for both fish and humans and that mediate disease states in the zebrafish that are identical to those found in human streptococcal infections, we will be able to identify common virulence strategies shared by a number of Gram-positive pathogens.