Resistance of Gram-negative bacteria to cephalosporins, as with other beta-lactam antibiotics, is a function of a combination of outer-membrane permeability, affinity and stability to beta-lactamases, and their activity against target sites (penicillin-binding proteins). Permeation through the outer-membrane is largely governed by the presence and properties of porins, which are water-filled channels facilitating the movement of hydrophilic molecules across the membrane. The properties of porins vary considerably between wild-type bacterial species, and their numbers (and hence the ability of a bacterial cell to exclude the antibiotic) may be reduced in strains with acquired resistance. In the case of cephalosporins, ability to cross the outer-membrane is related to physico-chemical properties such as molecular size, hydrophobicity and the number and charge of ionised groups. Thus, for example, dianionic compounds have in general lower permeability rates than dipolar cephalosporins. These relationships are discussed in detail. The phenotypically expressed susceptibility of a particular bacterial strain to a cephalosporin is brought about by a dynamic combination of permeation, the ability of the agent to resist degradation or binding to the beta-lactamases in the periplasmic space which act upon the relatively low concentration of cephalosporin present there, and target affinity. The interplay of these factors is discussed.