Treatment failures in patients with VAP are a complex issue and form a major challenge for clinicians. The following key elements inherent to a rational approach to treatment failures have been elucidated: (1) the presence of treatment failure must be thoroughly defined and assessed; (2) the many causes behind treatment failures must be realized, particularly the possibility of pneumonia-related and extrapulmonary reasons; (3) the recognition of different patterns of treatment failures as a useful framework for decisions about modalities and intensity of diagnostic reassessment; and (4) the establishment of a protocol for the search of pulmonary and extrapulmonary sites of infection and noninfectious causes of nonresponse. Only such a rational approach precludes the adverse effects of blind empiricism, which always implies a dangerous and costly overtreatment. Many issues related to treatment failures remain unsettled, and efforts will have to be made in the future to improve current clinical attitudes to treatment failures in VAP.