Although substantial progress has been made in understanding the clinical, radiological, and pathological manifestations of fibrosing interstitial lung diseases (ILD), it remains difficult for the clinician to predict the clinical course or the response to therapy for the subtypes of ILD, even from individual to individual with the same diagnosis. This article reviews the genetic and environmental causes of pulmonary fibrosis, specifically focusing on genetic and epigenetic variants of MUC5B and several types of ILD, to discuss why only some individuals with the MUC5B promoter polymorphism develop pulmonary fibrosis. Once we discover how these genetic and epigenetic risks lead to the development of ILD, we and others can apply these discoveries to: (1) identify individuals at risk of developing ILD, (2) diagnose the condition at an earlier stage, (3) identify novel mechanisms that cause ILD, and (4) eventually develop personalized therapeutic strategies for intervention.