Differences in antibiotic breakpoints have resulted from differences in clinical practice and in interpretation of the parameters that are considered when breakpoints are set. Differences in the first of these are less common for newer agents, whereas differences in the latter could be resolved by consensus discussions. Greater difficulty arises when common pathogens acquire resistance, especially when this occurs by degrees, as has happened with penicillin for gonococci and the pneumococci, and for the fluoroquinolones in relation to a wide variety of bacterial species. Changes to breakpoints under such circumstances should be introduced only after the most careful consideration and the education of diagnostic microbiologists and clinicians.