ABSTRACT Streptococcus mutans has been strongly implicated as the principal etiological agent in human dental caries. It is also an important agent of infective endocarditis. S. mutans colonizes the oral cavity through the formation of diverse, multispecies biofilms on the tooth surface, known as dental plaque. S. mutans flourishes in the hostile environment of the oral cavity by responding efficiently to various environmental fluxes, including severe nutrient limitation, fluctuations in pH and temperature. Exposure of bacteria to these adverse environments can induce a stress tolerance response through expression of a wide variety of proteins that provide cross-protection against environmental challenges. The caseinolytic protease (Clp) family proteins, which contain HSP100/Clp chaperones and the ClpP protease, constitute the core of bacterial protein quality control systems involved in thermal and other stress responses. ClpP, a small cytoplasmic serine protease, associates with a partner ATPase chaperone to form a functional complex that specifically targets damaged or mis-folded proteins for degradation (collectively known as regulated proteolysis) during stresses. While ClpP degrades the damaged protein, the ATPase component determines the substrate specificity. Like other Firmicutes, streptococci encode five Clp ATPases and only three of these (ClpC, ClpE, and ClpX) interact with ClpP to form active complexes. ClpP is the primary intracellular protease that is required for stress tolerance response, bacteriocin production, and biofilm formation among others While ClpX/P is the major player, we recently found that ClpE/P is also involved in protein quality control in streptococci. However, the molecular mechanism of substrate recognition and degradation by ClpX/P and ClpE/P are not well understood in these organisms. In fact, very little is known about protein quality control and their role in virulence in streptococci. Our long-term goal is to understand the molecular mechanisms of regulated proteolysis in S. mutans and other oral streptococci.