This review summarises the changing epidemiology of resistance to cephalosporins and fluoroquinolones among the Enterobacteriaceae since the 1980s and its potential impact on prescribing choices now and in the immediate future. Whilst multiresistant Enterobacteriaceae are not a novel problem for high-risk hospital units, such as intensive care, the emergence of Escherichia coli co-expressing extended-spectrum beta-lactamases, such as CTX-M types, along with fluoroquinolone resistance in the community is starting to impact in situations where cephalosporins and ciprofloxacin were seen as reliable first-line choices. The reduction in effective options to treat these infections, particularly of the urinary tract and bacteraemia, is likely to result in increased prescribing of carbapenems, thus generating further selective pressure for carbapenemases and other mechanisms of carbapenem resistance in the future.