This article reviews research on acute inflammatory lung injury induced by gastric aspiration in animal models. The innate pulmonary inflammatory response and the severity of lung injury depend strongly on the nature of the gastric aspirate: hydrochloric acid (ACID, pH 1.25), small non-acidified gastric particles (SNAP), or combined acid and small gastric particles (CASP). The "two-hit" pathology of CASP aspiration in rodents is directly relevant for clinical gastric aspiration, and may lead to an increased risk for progression to clinical acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS). Rodents (rats, mice) with CASP aspiration have more severe acute pulmonary injury based on decreased PaO2/FiO2 ratios and increased albumin levels in bronchoalveolar lavage (BAL) compared to rodents given ACID or SNAP alone. Rodents given CASP also have increased inflammation based on levels of cytokines and chemokines in BAL during the 48 hr period post-aspiration. Recent research has used hierarchical cluster analysis and statistical modeling to define more specific correlations between lavaged inflammatory mediators and lung injury severity in rodents with ACID, SNAP, and CASP aspiration. Studies in transgenic murine models (e.g., MCP-1 (-/-) mice) have also been done to help assess the functional importance of particular mediators in aspiration injury. In addition to reviewing the effects of "two-hit" aspirates like CASP, this article also describes research on combination injuries where a second injury inducer (hyperoxia, lung contusion from blunt chest trauma, or instilled E. coli bacteria) is present concurrently with gastric aspiration. The concept of multi-hit injury to the lungs has major clinical significance. A single insult such as acid aspiration may be relatively well tolerated by the pulmonary parenchyma, but the presence of a concurrent or subsequent second insult such as particulate aspiration, hyperoxia, or pulmonary bacterial infection may lead to profound respiratory dysfunction with physiological attributes of ALI/ARDS.