The Streptococcus mutans Cid/Lrg system represents an ideal model to study how this organism withstands various stressors encountered in the oral cavity. Mutation of lrgAB renders S. mutans more sensitive to oxidative, heat, and vancomycin stresses. Here, we have performed a comprehensive proteomics experiment using label-free quantitative mass spectrometry to compare the proteome changes of wild type UA159 and lrgAB mutant strains in response to these same stresses. Importantly, many of identified proteins showed either a strikingly large fold-change, or were completely suppressed or newly induced in response to a particular stress condition. Notable stress proteome changes occurred in a variety of functional categories, including amino acid biosynthesis, energy metabolism, protein synthesis, transport/binding, and transcriptional/response regulators. In the non-stressed growth condition, mutation of lrgAB significantly altered the abundance of 76 proteins (a fold change >1.4, or <0.6, p-value <0.05) and several of these matched the stress proteome of the wild type strain. Interestingly, the statistical correlation between the proteome changes and corresponding RNA-seq transcriptomic studies was relatively low (rho(ρ) <0.16), suggesting that adaptation to a new environment may require radical proteome turnover or metabolic remodeling. Collectively, this study reinforces the importance of LrgAB to the S. mutans stress response.