Etch-and-rinse adhesives are among the oldest resin bonding systems, consisting of three steps: acid-etching, priming, and adhesive application. Acid-etching with 32-37% phosphoric acid etches enamel and dentin, kills bacteria, and inhibits matrix metalloproteinases (MMPs). Primers, usually water and HEMA-rich, expand the collagen meshwork and wet collagen with hydrophilic monomers. Water can re-expand dried dentin and serve as a vehicle for protease inhibitors or cross-linking agents, enhancing bond durability. Future primers may use ethanol or other solvents to dehydrate and inhibit MMPs, improving bond durability. Solvent-free adhesives can seal resin-dentin interfaces with hydrophobic resins containing fluoride and antimicrobial compounds. Etch-and-rinse adhesives produce stronger, more durable resin-dentin bonds than 1- or 2-step adhesives. Incorporating protease inhibitors in etchants and cross-linking agents in primers can enhance bond durability. The therapeutic potential of etch-and-rinse adhesives remains underexploited. The first marketed etch-and-rinse adhesive was Clearfil Bond System-F in 1978. Early use of "dry bonding" led to low resin-dentin bond strengths and increased microleakage. "Wet-bonding" improved bond strength and reduced post-operative pain. Dentin bonding is a form of tissue engineering, creating hybrid layers that are biocomposite structures. Over time, hybrid layers degrade due to collagen breakdown by MMPs, reducing bond strength. Studies show that resin-dentin bonds can degrade over months to years, but some adhesives maintain strength over time. The stability of bonds is influenced by peripheral enamel seals and functional stress. Endogenous MMPs can degrade collagen fibrils, and chelation or cross-linking agents can inhibit them. Protease inhibitors and cross-linking agents in primers can enhance bond durability. Ethanol wet-bonding can improve bond durability by dehydrating dentin and reducing nanoleakage. Solvent-free adhesives offer therapeutic benefits by reducing water sorption and enhancing bond durability. The use of therapeutic agents in adhesives can improve bond strength and reduce leakage. Overall, etch-and-rinse adhesives offer therapeutic flexibility through their three-step process, allowing for multiple functions and improved bond durability. The full potential of these adhesives for therapeutic use is yet to be fully realized.Etch-and-rinse adhesives are among the oldest resin bonding systems, consisting of three steps: acid-etching, priming, and adhesive application. Acid-etching with 32-37% phosphoric acid etches enamel and dentin, kills bacteria, and inhibits matrix metalloproteinases (MMPs). Primers, usually water and HEMA-rich, expand the collagen meshwork and wet collagen with hydrophilic monomers. Water can re-expand dried dentin and serve as a vehicle for protease inhibitors or cross-linking agents, enhancing bond durability. Future primers may use ethanol or other solvents to dehydrate and inhibit MMPs, improving bond durability. Solvent-free adhesives can seal resin-dentin interfaces with hydrophobic resins containing fluoride and antimicrobial compounds. Etch-and-rinse adhesives produce stronger, more durable resin-dentin bonds than 1- or 2-step adhesives. Incorporating protease inhibitors in etchants and cross-linking agents in primers can enhance bond durability. The therapeutic potential of etch-and-rinse adhesives remains underexploited. The first marketed etch-and-rinse adhesive was Clearfil Bond System-F in 1978. Early use of "dry bonding" led to low resin-dentin bond strengths and increased microleakage. "Wet-bonding" improved bond strength and reduced post-operative pain. Dentin bonding is a form of tissue engineering, creating hybrid layers that are biocomposite structures. Over time, hybrid layers degrade due to collagen breakdown by MMPs, reducing bond strength. Studies show that resin-dentin bonds can degrade over months to years, but some adhesives maintain strength over time. The stability of bonds is influenced by peripheral enamel seals and functional stress. Endogenous MMPs can degrade collagen fibrils, and chelation or cross-linking agents can inhibit them. Protease inhibitors and cross-linking agents in primers can enhance bond durability. Ethanol wet-bonding can improve bond durability by dehydrating dentin and reducing nanoleakage. Solvent-free adhesives offer therapeutic benefits by reducing water sorption and enhancing bond durability. The use of therapeutic agents in adhesives can improve bond strength and reduce leakage. Overall, etch-and-rinse adhesives offer therapeutic flexibility through their three-step process, allowing for multiple functions and improved bond durability. The full potential of these adhesives for therapeutic use is yet to be fully realized.