The wetness of dentin surfaces, the presence of pulpal pressure, and the thickness of dentin are extremely important variables during bonding procedures, especially when testing bond strength of adhesive materials in vitro with the intention of simulating in vivo conditions. The ultimate goal of a bonded restoration is to attain an intimate adaptation of the restorative material with the dental substrate. This task is difficult to achieve as the bonding process is different for enamel and for dentin-dentin is more humid and more organic than enamel. While enamel is predominantly mineral, dentin contains a significant amount of water and organic material, mainly type I collagen. This humid and organic nature of dentin makes this hard tissue very challenging to bond to. Several other substrate-related variables may affect the clinical outcome of bonded restorations. Bonding to caries-affected dentin is hampered by its lower hardness and presence of mineral deposits in the tubules. Non-carious cervical areas contain hypermineralized dentin and denatured collagen, which is not the ideal combination for a bonding substrate. Physiological transparent root dentin forms without trauma or caries lesion as a natural part of aging. Similar to the transparent dentin observed underneath caries lesions, the tubule lumina become filled with mineral from passive chemical precipitation, making resin hybridization difficult. An increase in number of tubules with depth and, consequently, increase in dentin wetness, make bonding to deeper dentin more difficult than to superficial dentin. While the application of acidic agents open the pathway for the diffusion of monomers into the collagen network, it also facilitates the outward seepage of tubular fluid from the pulp to the dentin surface, deteriorating the bonding for some of the current adhesives. Some dentin desensitizers have shown some promise as they can block dentinal tubules to treat and prevent sensitivity and simultaneously blocking the tubular fluid from flowing to the surface. A new approach to stop the degradation of dentin-resin interfaces is the use of MMP inhibitors. Although still in an early phase of in vitro and clinical research, this method is promising.