Among the inflammatory myopathies, anti-tRNA-synthetase syndrome (ASyS) is a severe autoimmune condition characterized by extramuscular involvement, affecting especially the lungs. ASyS specific serological markers are anti-tRNA-synthetase autoantibodies, among which anti-histidyl-tRNA-synthetase is the most common. In the past decades, ASyS has been distinguished by unique histological features attributed to a specific pathogenesis. Research has highlighted the role of environmental factors and infections as possible triggers. Tissue modifications of histidyl-tRNA-synthetase (HisRS) expression might be responsible for the recruitment and activation of both innate and adaptive immune cells. HisRS not only acts through antigenic properties, but also through many others, including chemoattraction, innate pathway activation, and cytokine-like functions. Favored by a certain genetic background, this whole activation of immunity results in widespread and specific tissue damage and finally leads to visible heterogeneous symptoms characterizing the disease state. Understanding the pathogenesis of ASyS is essential to improving patient care by identifying biomarkers and designing new therapeutic strategies accordingly. Therefore, this review details the recent hypotheses concerning the dynamic of ASyS pathogenesis with the aim of enlightening the development of new therapeutic axes in the future.