Substantial changes in disease burden, prevalence of comorbid conditions, or other factors that may affect the etiology of pneumonia have occurred since the last systematic set of etiology studies in children were undertaken. For example, most of the evidence on which current empiric treatment algorithms for pneumonia in developing countries are based was collected before the human immunodeficiency virus (HIV) pandemic and in the absence of antiretroviral treatment of HIV-infected children, before recent substantial successes in malaria control, and before the widespread deployment of Hib and pneumococcal conjugate vaccines. Furthermore, lower rates of very severe malnutrition and increased urbanization and crowding may also impact the etiology of pneumonia and make pneumonia etiology data obtained in the 1980s less relevant to policy today. Simply put, continued use of clinical algorithms based on the assumption that predominant causes of severe pneumonia are almost always H. influenzae and S. pneumoniae may lead to treatments that are not appropriate for a child’s actual infection and will miss the opportunity to guide vaccine development against important new or unrecognized pathogens.