The cephalosporin antibiotics have become a major part of the antibiotic formulary for hospitals in affluent countries. They are prescribed for a wide variety of infections every day. Their undoubted popularity relies upon lesser allergenic and toxicity risks as well as a broad spectrum of activity. It is the latter feature, however, that encourages the selection of microorganisms that are resistant to these agents. There are long-term implications for the treatment and control of this heterogeneous group of superinfections. When clinicians evaluate a septic patient, it is understandable that they choose empirical therapy with a cephalosporin whilst awaiting microbiology and other tests, since bacterial identification and antimicrobial testing still usually require 24-48 h. The broad-spectrum capability of these drugs, however, encourages rapid overgrowth of some microorganisms that are neither eliminated nor inhibited by therapy. These organisms not only have pathogenic potential, they may also be multiply resistant to antibiotics. This review discusses the evidence that cephalosporin usage is the most important factor in the selection and propagation of microorganisms such as Clostridium difficile, methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococci, multiply resistant coliforms and vancomycin-resistant enterococci, the continuing increase of which threatens the future of antimicrobial therapy.