Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain two of the most commonly diagnosed nosocomial infections. Both are responsible for significant morbidity and mortality in hospitalized patients. The development of HAP and VAP is related to bacterial colonization of the oropharynx (and endotracheal tube in VAP) with subsequent microaspiration and development of clinical infection. Diagnosis is made based on the clinical presentation and can be confirmed by obtaining either noninvasive or invasive microbiology culture specimens. Decisions addressing initiation of antimicrobial therapy can be divided into clinical and bacteriological strategies. These strategies differ in the criteria used to determine the timing of empiric therapy, with the clinical strategy basing the decision on radiographic evidence of infection plus clinical signs and symptoms and the bacteriological strategy requiring growth of pathogens above a certain threshold from invasively obtained culture specimens. Despite the delineated pathways, these decisions remain multifactorial and should also include consideration of patient-related factors, such as immunocompetence, the risk of multidrug-resistant infection, and overall clinical condition. Patients with risk factors or signs of clinical decompensation should have empiric therapy initiated at a lower threshold. However, when possible, therapy should be directed at a confirmed infection following a positive culture result. Decisions regarding specific empiric regimens should be based on the local prevalence of infectious microorganisms along with their associated antimicrobial susceptibilities. Patients deemed at risk of infection with multidrug-resistant pathogens merit broader spectrum therapy, and immunosuppressed patients should have consideration of antifungal coverage.