The major emphasis in new drug design within the β-lactam family has been on compounds less susceptible to hydrolysis by β-lactamases and on combinations containing an enzyme-labile drug plus a β-lactamase inhibitor. The introduction of such new compounds into clinical use has been followed by the discovery of novel mechanisms of resistance among gram-negative bacteria. These include the appearance of new enzymes, many of which are derivatives of older β-lactamases. In addition, genes for certain broad-spectrum enzymes previously restricted to chromosomal sites have moved onto plasmids. There is now a greater appreciation of how alterations in enzyme expression—either alone or in concert with changes in drug permeation—can also lead to resistance. Clearly, recent events in the development of new β-lactam agents have led to a new phase in the understanding of β-lactam resistance.