The penetration of antibiotics into the microbial cell is reviewed from the standpoint of the structure and function of the several types of membranes which constitute permeability barriers to the passage of hydrophilic molecules. It is clear that little is actually known about the mechanisms by which the majority of antibiotics gain access to their site of action within the target cell. Sufficient evidece is at hand to indicate that resistance to several groups of antibiotics is determined by changes in the permeability of the cell membranes, the genes for which are often carried on R-plasmids. The importance of studies to determine the precise mechanisms by which each type of antibiotic permeates the membrane of the bacterial cell is stressed by a discussion of several approaches to enhancing antibiotic permeation through manipulation of either the drug or the target cell based on knowledge of the uptake mechanisms.