The article reviews the state-of-the-art etch-and-rinse adhesive systems, which are the oldest multi-generation evolution of resin bonding systems. These systems involve three steps: acid-etching, priming, and application of a separate adhesive. Each step has multiple therapeutic goals. Acid-etching with 32-37% phosphoric acid not only etches enamel and dentin but also kills residual bacteria and inhibits matrix metalloproteinases (MMPs) in dentin. Primers, typically water and HEMA-rich solutions, ensure the expansion of collagen fibrils and wet the collagen with hydrophilic monomers. Solvent-free adhesives can seal resin-dentin interfaces with hydrophobic resins, potentially increasing bond durability. The article discusses the therapeutic potential of each step, including the use of chelators to inactivate MMPs, protein cross-linking agents, and specific and nonspecific inhibitors of proteases. Ethanol wet-bonding is highlighted as a technique that enhances bond strength and reduces nanoleakage by chemically dehydrating acid-etched dentin. The article concludes by emphasizing the therapeutic flexibility of 3-step etch-and-rinse adhesives and the need for manufacturers to fully exploit their potential.The article reviews the state-of-the-art etch-and-rinse adhesive systems, which are the oldest multi-generation evolution of resin bonding systems. These systems involve three steps: acid-etching, priming, and application of a separate adhesive. Each step has multiple therapeutic goals. Acid-etching with 32-37% phosphoric acid not only etches enamel and dentin but also kills residual bacteria and inhibits matrix metalloproteinases (MMPs) in dentin. Primers, typically water and HEMA-rich solutions, ensure the expansion of collagen fibrils and wet the collagen with hydrophilic monomers. Solvent-free adhesives can seal resin-dentin interfaces with hydrophobic resins, potentially increasing bond durability. The article discusses the therapeutic potential of each step, including the use of chelators to inactivate MMPs, protein cross-linking agents, and specific and nonspecific inhibitors of proteases. Ethanol wet-bonding is highlighted as a technique that enhances bond strength and reduces nanoleakage by chemically dehydrating acid-etched dentin. The article concludes by emphasizing the therapeutic flexibility of 3-step etch-and-rinse adhesives and the need for manufacturers to fully exploit their potential.