Over the past decade, the identification of cancer-associated factors has been a subject of primary interest not only for understanding the basic mechanisms of tumorigenesis but also for discovering the associated therapeutic targets. However, aminoacyl-tRNA synthetases (ARSs) have been overlooked, mostly because many assumed that they were simply 'housekeepers' that were involved in protein synthesis. Mammalian ARSs have evolved many additional domains that are not necessarily linked to their catalytic activities. With these domains, they interact with diverse regulatory factors. In addition, the expression of some ARSs is dynamically changed depending on various cellular types and stresses. This Analysis article addresses the potential pathophysiological implications of ARSs in tumorigenesis.