Group A Streptococcus (GAS) is a fastidious microorganism that has adapted to a variety of niches in the human body by sensing its surroundings and modifying its metabolism to elicit a wide array of diseases. The Phosphoenolpyruvate Phosphotransferase System (PTS) is a primary mechanism by which many bacteria transport sugars and sense the carbon state of the cell. The PTS uses the non-sugar specific general' proteins EI and Hpr, and sugar-specific membrane-spanning proteins (EIIs) for the PTS-mediated uptake of each sugar. The role of PTS in carbohydrate metabolism in GAS was investigated by generating a &Delta;ptsI mutant (EI deficient) in three different strains belonging to M1T1 and one of M4 GAS. All &Delta;<italic>ptsI</italic> mutant strains tested were unable to grow on multiple carbon sources (PTS and non-PTS). Complementation with <italic>ptsI</italic> expressed under its native promoter in single copy was able to rescue the growth defect of the mutant. Additional studies analyzing the role of PTS in pathogenesis of GAS, showed a hypervirulent' phenotype in the absence of ΔptsI from M1T1 using soft tissue model of infection. The appearance of significantly larger and more severe ulcerative lesion observed in mice infected by ΔptsI was correlated with increased transcript levels of sagA and early Streptolysin S (SLS) activity during exponential phase growth. The role of SLS in increased pathogenesis of ΔptsI was investigated by the creation of a double mutant strain (ΔptsI sagB) that lacks the ability to secrete SLS. The infection of mice with a ΔptsI sagB double mutant resulted in a lesion comparable to either a wild type or a sagB mutant alone. In addition to SLS, it was found that PTS influences the secretion of cysteine protease SpeB and the ability of GAS to produce capsule. This regulatory effect was found to be dependent on the status of sensor kinase (CovS) of the CovR/S two-component system. Moreover, PTS was shown to phosphorylate PTS regulatory domains (PRD) of a global virulence regulator, Mga, resulting in alteration of its regulon in both M1T1 and M4 background, suggesting the ability of GAS to alter expression of Mga regulon in response to carbohydrate availability. Overall, our studies indicate that a functional PTS is important for utilizing PTS and non-PTS sugars and influences virulence during GAS infection.