The ability of a pathogen to evade neutrophil phagocytic killing mechanisms is critically important for dissemination and establishment of a systemic infection. Understanding how pathogens overcome these innate defenses is essential for the development of optimal therapeutic strategies for invasive infections. CpsY is a conserved transcriptional regulator previously identified as an important virulence determinant for systemic infection of Streptococcus iniae. While orthologs of CpsY have been associated with the regulation of methionine metabolism and uptake pathways, CpsY additionally functions in protection from neutrophil-mediated killing. S. iniae does not alter neutrophil phagosomal maturation but instead is able to adapt to the extreme bactericidal environment of a mature neutrophil phagosome, a property dependent upon CpsY. This CpsY-dependent adaptation appears to involve stabilization of the cell wall through peptidoglycan O-acetylation and repression of cellular autolysins. Furthermore, S. iniae continues to be a powerful model for investigation of bacterial adaptations during systemic streptococcal infection.