The lack of response to antimicrobial treatment represents a challenge for clinicians due to the increased difficulty of adequate management and greater mortality. Mortality is increased threefold a to fivefold or even more in nonresponding pneumonia and depends on the cause. Reasons for treatment failure are classified as infectious in 40% of cases, noninfectious in 15% of cases, and unknown in the remaining cases. The microorganisms most often related to antimicrobial failure are Streptococcus pneumoniae, Pseudomonas species, Legionella pneumophila, and Staphylococcus aureus. The diagnostic approach recommended should include a complete epidemiological and clinical re-evaluation with respiratory samples obtained by bronchoscopy. Samples from such invasive techniques showed a diagnostic yield of 41%, although the impact of this type of sampling on outcome has not been demonstrated. Radiographic studies with chest radiography or computed tomography are also recommended. The role of inflammatory response of the host against microorganisms is a topic of recent investigations. Biological markers are easy to measure and reflect inflammation, so this is a promising approach to predicting and evaluating clinical responses. Because of treatment failure, empirical antimicrobial therapy should include antimicrobials to cover a broader spectrum of microorganisms, including those resistant to treatment.