The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program was a global, longitudinal antimicrobial resistance surveillance network of more than 100 medical centers worldwide monitoring the susceptibility of meropenem and selected other broad-spectrum comparator agents. In 1999, and from 2000 through 2008, a total of 10 or 15 United States (USA) medical centers each forwarded 200 nonduplicate clinical isolates from serious infections to a central processing laboratory. Over the 10-year period of this surveillance program, the activity of meropenem and an average of 11 other antimicrobial agents were assessed against a total of 27 289 bacterial isolates using Clinical and Laboratory Standards Institute reference methods. Meropenem consistently demonstrated low resistance rates against Enterobacteriaceae species isolates through 2008 and did not exhibit a widespread change in resistance rates over the monitored interval. In fact, the incidence of emerging carbapenemase-producing (KPC-type) Klebsiella spp. showed a decline in 2008 compared to the steeply increasing rates observed from 2004 to 2007. Moreover, the KPC serine carbapenemases have spread to other Enterobacteriaceae species monitored by the MYSTIC Program. Greatest increases in antimicrobial resistance rates were observed for the fluoroquinolones (ciprofloxacin, levofloxacin) among all species monitored by the MYSTIC Program. Current susceptibility rates for meropenem when tested against prevalent pathogens were Pseudomonas aeruginosa (439 strains, 85.4% susceptible), Enterobacteriaceae (1537 strains, 97.3% susceptible), methicillin-susceptible staphylococci (460 strains, 100.0% susceptible), Streptococcus pneumoniae (125 strains, 80.2% at meningitis susceptibility breakpoints), other streptococci (159 strains, 90.0-100.0% susceptible), and Acinetobacter spp. (127 strains, 45.7% susceptible), the widest spectrum among beta-lactams tested in 2008 and throughout the last decade. Continued local surveillance of broad-spectrum agents following the completion of the MYSTIC Program (USA) appears critical to detect emerging resistances among pathogens causing the most serious infections requiring carbapenem agents.