Abstract: Interstitial lung diseases (ILDs) are a group of diverse pulmonary disorders characterized by various patterns of inflammation and fibrosis in the interstitium of the lung. There are no specific diagnostic methods for ILDs currently and various serum biomarkers, including Krebs von den Lungen-6 (KL-6), have been tested for their use in diagnosing ILDs. However, the pathophysiological role of KL-6 in patients with ILDs is not yet very clear. KL-6 is high-molecular-weight glycoprotein and moderately expressed in type Ⅱ pneumocytes and respiratory bronchiolar epithelial cells. KL-6 has been found to have an association with various types of diseases such as cancers, some neonatal lung diseases, ILDs, and acute lung injury. In this article, we review the structure of KL-6 and the relationship between the elevation of KL-6 and the etiology, progression, treatment evaluation, and prognosis of ILDs.