Interstitial lung disease (ILD) is an umbrella term for many different disease entities causing inflammation and fibrosis of the lung parenchyma. These can be broadly divided into five categories based on etiology (1): (1) ILD related to a distinct primary disease (e.g., sarcoidosis), (2) ILD related to environmental factors (e. g., hypersensitivity pneumonitis), (3) ILD induced by drugs or irradiation, (4) idiopathic interstitial pneumonias (e.g., idiopathic pulmonary fibrosis), and (5) ILD related to connective tissue diseases (CTD) (1). While all these entities require thorough and multidisciplinary assessment to ascertain a diagnosis, establish the need for diagnostic procedures, and recommend a patient-specific treatment plan, ILDs associated with systemic diseases are particularly challenging. In many cases, optimal treatment for involvement of other organ systems needs to be balanced with the choice of ILD-directed therapies. For the highly heterogeneous group of patients who cannot be given a definite diagnosis of an autoimmune rheumatic disease but who demonstrate certain clinical, radiographic, and/or serological features suggestive of a CTD, the term interstitial pneumonia with autoimmune features (IPAF) has been coined (2), but its clinical value remains to be defined. Due to its complexity, management of ILDs associated with systemic disease requires multidisciplinary care, including pulmonologists, rheumatologists, and radiologists, often with critical input from other specialties, such as pathologists, dermatologists, or neurologists. In this Research Topic, we hope to present novel research and state-of-the-art reviews as relevant to the care of patients with ILD and systemic diseases.