Some twenty years ago, Van der Waay et al. [1, 2] demonstrated that the nature of the resident intestinal flora determines host resistance to orally administered gram-negative bacteria. In mice treated with certain oral antibiotics, much of their intestinal flora is eliminated. When these animals are challenged with orally administered gram-negative microbes, the animals become colonized after significantly lower doses of bacteria, than when bacteria were fed to normal animals. This phenomenon was called colonization resistance (CR), and defined as the number of orally administered bacteria that results in persistent colonization of 50% of the challenged animals. The CR of antibiotic-treated animals is significantly lower than the CR of controls. For example, using Escherichia coli, the CR of normal animals was 109 organisms and that of antibiotic-treated animals only 102 organisms. It was hypothesized that the resident anaerobic microorganisms possess a CR factor. Subsequent experiments demonstrated that certain antibiotics (e.g. ampicillin) deplete both the aerobic and anaerobic intestinal flora and markedly diminish the CR of the treated animal. Other antibiotics (e.g. nalidixic acid, polymyxin B, and trimethoprim-sulfamethoxazole [TMP- SMX]) selectively depress aerobic flora and appear not to change the animal’s CR. Van der Waaij and others reasoned that antibiotics that are mainly active against aerobes, such as TMP-SMX, and do not influence the CR may be used to prevent infection in susceptible patients. Because they eliminate potential pathogens from the mucosal surfaces without affecting anaerobes, they leave the CR intact, thus preventing colonization by bacteria from the hospital environment (selective decontamination of the digestive tract, SDD).