Cell wall impermeability is a major determinant of the susceptibility of gram-negative bacilli to beta-lactam antibiotics. The outer membrane, which beta-lactam agents cross via pores composed of porin proteins, is the major individual barrier in the wall structure but does not of itself exclude these antibiotics. Rather, it slows their influx to a level that the periplasmic clearance mechanisms may manage to contain. The clearance mechanisms include hydrolysis and perhaps covalent binding by beta-lactamases and nonessential penicillin-binding proteins. The balance between uptake and clearance determines the fate of the cell, rather than one or the other factor alone. It is possible to represent this interplay mathematically for Escherichia coli, but Pseudomonas aeruginosa presents a more ambivalent picture. Moreover, the relations among porin quantity, permeability, and resistance are much better established for E. coli than for P. aeruginosa, and the possible existence of additional barrier layers--besides the outer membrane--in the latter species cannot be excluded.