Minimum inhibitory concentrations (MICs) of most lipophilic agents tend to be much higher against gram-negative than gram-positive bacteria. Multidrug efflux pumps that traverse both the inner and outer membranes make a major contribution to this intrinsic resistance of gram-negative bacteria. Such a pump is composed of at least three components, is energized by the proton-motive force, and can pump out not only an extremely wide variety of detergents, dyes, and antibiotics, but also those compounds, such as β-lactams, that do not easily cross the cytoplasmic membrane. Increased expression of these pumps can raise the MICs to an impressive level. For example, 80% of carbenicillin-resistant clinical isolates of Pseudomonas aeruginosa from the British Isles owed their resistance to overexpression of an efflux pump and had carbenicillin MICs that were up to 2,000 times higher than that of the pump-deficient mutant strain.