Four generations of total-etch (fourth, fifth) and self-etching (sixth, seventh) bonding agents for use with resin composites are commercially available in the United States. Innovations in bonding agents include: filled systems, release of fluoride and other agents, unit dose, self-cured catalyst, option of etching with either phosphoric acid or self-etching primer, and pH indicators. Factors that can affect in vitro bond strength to human dentin include substrate (superficial dentin, deep dentin; permanent versus primary teeth; artificial carious dentin), phosphoric acid versus acidic primers, preparation by air abrasion and laser, moisture, contaminants, desensitizing agents, astringents, and self-cured restorative materials. This article reviews studies conducted at the Houston Biomaterials Research Center from 1993 to 2003. Results show that in vitro bond strengths can be reduced by more than 50% when bonding conditions are not ideal.