Many current therapeutic drugs, e.g., antibiotics and peptide drugs, are impermeable to outer tissue barriers. Drug delivery of impermeable drugs through such barriers is currently one of the major interests in pharmaceutical research. New classes of absorption enhancers provide rapid absorption in the gastrointestinal tract or skin, with no side effects. This review covers the history of enhancer research, an overview of a variety of absorption enhancers, the nature of enhancing action, and site specificity. The final section focuses on the mechanisms of enhancer action which transiently abolishes or reverses barrier resistance, from the viewpoints of the lipid bilayer barrier containing SH proteins, as well as transcellular/paracellular pathways. Fully understanding these mechanisms is of importance for therapeutic applications.