Pneumonia and its sequelae, acute lung injury, present unique challenges for pulmonary and critical care healthcare professionals, and these challenges have recently garnered global attention due to the ongoing Sars-CoV-2 pandemic. One limitation to translational investigation of acute lung injury, including its most severe manifestation (acute respiratory distress syndrome, ARDS) has been heterogeneity resulting from the clinical and physiologic diagnosis that represents a wide variety of etiologies. Recent efforts have improved our understanding and approach to heterogeneity by defining sub-phenotypes of ARDS although significant gaps in knowledge remain. Improving our mechanistic understanding of acute lung injury and its most common cause, infectious pneumonia, can advance our approach to precision targeted clinical interventions. Here, we review the pathogenesis of pneumonia and acute lung injury, including how respiratory infections and lung injury disrupt lung homoeostasis, and provide an overview of respiratory microbial pathogenesis, the lung microbiome, and interventions that have been demonstrated to improve outcomes—or not—in human clinical trials.