Although the distal small intestine has less lumenal and apical proteolytic activities, it has high activities of some apical peptidases. Colonic proteolytic activities are substantial, but their nature is less understood. The small intestine has di- and tripeptide transporter, facilitating absorption, and P-glycoprotein, an efflux pump suggested to limit absorption of small peptides. Several peptide and nonpeptide drugs have higher absorption in the ileum; however, enhancement on their absorption by enhancers varies from site to site. Specific delivery systems can target drugs to the distal intestine utilizing distinct regional pHs and specific microbial enzymes, but the key is how to achieve a reliable release.