There is no consensus on the definition of treatment failure. It is usually based on clinical signs, although microbiological and other biological markers may prove of value in the future. The major risk factors associated with treatment failure include an inadequate antimicrobial spectrum of the prescribed antibiotic and lack of, or insufficient, control of the source of the infection. In certain patient subpopulations additional specific factors may play a role. Reported treatment failure rates are unacceptably high, reaching up to 64%. Treatment failure is highly clinically relevant, as indicated by the associated constant finding of significantly increased length of hospital stay, higher mortality and greater healthcare costs. Proposed future initiatives include consensus statements on validated variables and definitions, both for general patient populations and specific subgroups. Investigation of the relative impact of modifiable risk factors may allow for the development of a treatment failure score for adequate stratification of individual cases. In patients in the high-risk group, initial broad-spectrum antimicrobial coverage, and modifications to doses and the dosing schedule should be considered.