Over the past 60 years, the use of successive generations of β-lactam antibiotics has selected successive generations of β-lactamase enzymes, each more potent than the last. Currently, rising problems include CTX-M extended-spectrum β-lactamases (ESBLs), plasmid-mediated AmpC β-lactamases and KPC carbapenemases in Enterobacteriaceae, while OXA- and metallo- carbapenemases are of growing importance in Acinetobacter spp. and (less so) in other non-fermenters. Escherichia coli isolates with CTX-M ESBLs are spreading multiresistance in the community and in hospitals, while carbapenemase-producing Acinetobacter spp., mostly from intensive care, are among the most multiresistant nosocomial bacteria known and are often susceptible only to polymyxins and, potentially, tigecycline. This review discusses the epidemiology and microbiology of these resistance problems, along with possible solutions.