Abstract: Knowledge of the natural history of ventilator-associated pneumonia (VAP) is crucial to identify patients at risk for failure to resolve VAP. Recognition of early markers of adequate response to therapy can help physicians to interfere in the process of care of those patients improving their trajectory, trying to attenuate morbidity associated with this nosocomial infection. Main clinical markers of resolution are temperature and pressure of oxygen to fraction of inspired oxygen. During the first 48 hours of therapy, when the results of cultures are available, resolution of fever and hypoxemia are easily evaluable variables able to discriminate patients failing to respond to therapy. Biochemical markers are also accurate; however, there is a lack of a specific marker of VAP. Most of the microorganisms involved in the etiology of VAP are eradicated during the first 72 hours of evolution. The main role of serial distal airways microbiological cultures, in patients failing to improve, is to exclude the presence of superinfection, coinfection, or relapse. Risk factors and causes for failure of therapy include the presence of acute respiratory distress syndrome, immunity of the host, inappropriate and inadequate antibiotic therapy in terms of delayed administration, poor penetration in the lung, and inadequate dosing. Microbial etiology also influences resolution of VAP being the presence of methicillin-resistant Staphylococcus aureus associated with a worse clinical outcome. Additionally, other sources of infectious and noninfectious diseases can interfere with the evolution of critically ill patients with VAP.