Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major health problems worldwide. Critical care physicians have long recognized that there are patients who progress poorly despite therapy while others do unexpectedly better than it might be predicted. It is now well accepted that these responses might be related to variations in the genome. However, little is known about the genes that are responsible for susceptibility and outcome in ALI and ARDS. The search for genetic variants determining susceptibility and predicting outcome is still a developing field. The identification of important associations between genotype and clinical outcomes will have an impact on the development of more efficient genotype- or phenotype-guided therapies for patients with ALI/ARDS. Using this point of view, we will discuss some of the advances in genetic association studies in relation to the occurrence and severity of ALI/ARDS. In addition, we will also discuss the strategic and medical implications of using genetic testing to detect or predict the occurrence and prognosis of ALI/ARDS.