Faropenem (FAR) is an orally available member of the penem class unique among carbapenems and other available β-lactams. This study compared FAR to cephalosporins and imipenem with respect to β-Iactamase (BLA) stability and emergence of resistance to <i>Staphylococcus aureus </i>and <i>Escherichia coli</i>. BLA stability was studied using enzyme preparations from sonicated/centrifuged 24-hour cultures of <i>E. coli, Enterobacter cloacae, Proteus vulgaris, Providencia rettgeri, Klebsiella pneumoniae, S. aureus, </i>and <i>Bacteroides fragilis</i> grown in the presence of 20 mg/l ampicillin or cephaloridine to induce penicillinase or cephalosporinase, respectively. Substrate hydrolysis was quantitated spectrophotometrically. Multistep acquisition of resistance was promoted by growing bacteria in broth containing 2-fold dilutions of antibiotic over 10 cycles. Aliquots from test tubes with visible growth provided the inoculum for the next series of dilutions. FAR as well as other cephalosporins tested were highly stable to penicillinase derived from <i>S. aureus </i>and <i>E. coli. </i>However, <i>E. coli</i>- and <i>P. vulgaris</i>-derived cephalosporinase hydrolyzed cephaloridine, cefaclor and cefotiam considerably, whereas FAR was highly stable. FAR was highly stable against hydrolysis by various BLAs prepared from four <i>B. fragilis</i> strains and the rate of FAR hydrolysis by metallo-BLA was 5 times lower than that for imipenem. Additionally, the acquisition of resistant <i>S. aureus </i>strains was less pronounced for FAR compared to other agents tested. MICs rose 8-fold after the 10th sub-MIC exposure, while MICs rose 16-, 31- and 512-fold for cefixime, cefazolin and cefaclor, respectively. <i>E. coli</i> shifts in MICs were moderate for all the agents tested. In conclusion, FAR is characterized by pronounced BLA stability compared to other cephalosporins and imipenem. Furthermore, a lower propensity for resistance development with FAR as compared to cephalosporins was observed.