Dental caries is a chronic infectious disease of multifactorial etiology that derives from the interplay among cariogenic bacteria on the dentition, the host diet, and other environmental exposures. Streptococcus mutans proliferates as a biofilm on the tooth surface, where it obtains nutrients and metabolizes fermentable dietary carbohydrates. The accumulation of lactic acid as a by-product of fermentation results in acidification of the plaque biofilm and demineralization of tooth enamel, marking the onset of decay. The ability of S. mutans to respond to environmental stresses presented by salivary flow, acid pH, oxidative stress, and changes in carbohydrate source and availability is essential for its survival and predominance in caries lesions. Importantly, S. mutans has evolved a network of regulators to integrate its cellular response to environmental change. Herein we describe the latest insights into global gene regulation in S. mutans, including mechanisms of signal transduction, carbon catabolite repression, and quorum-sensing. An improved understanding of these regulatory networks can provide a basis for novel therapeutic applications aimed at treating and/or preventing caries.