The objective of this review is to summarize our understanding of the role of host matrix metalloproteinases (MMPs) in the caries process and to discuss new therapeutic avenues. MMPs hydrolyze components of the extracellular matrix and play a central role in many biological and pathological processes. MMPs have been suggested to play an important role in the destruction of dentin organic matrix following demineralization by bacterial acids and, therefore, in the control or progression of carious decay. Host-derived MMPs can originate both from saliva and from dentin. They may be activated by an acidic pH brought about by lactate release from cariogenic bacteria. Once activated, they are able to digest demineralized dentin matrix after pH neutralization by salivary buffers. Furthermore, the degradation of SIBLINGs (Small Integrin-binding Ligand N-linked Glycoproteins) by the caries process may potentially enhance the release of MMPs and their activation. This review also explores the different available MMP inhibitors, natural or synthetic, and suggests that MMP inhibition by several inhibitors, particularly by natural substances, could provide a potential therapeutic pathway to limit caries progression in dentin.