The 20 aminoacyl tRNA synthetases arose early in evolution as agents of decoding genetic information for protein synthesis in the cytoplasm. And yet, in humans they are associated with many human diseases where no defect in protein synthesis is found. These diseases and other physiological connections are associated with their re-purposing, through secreted and nuclear forms. These associations are correlated with their long evolutionary history, during which the synthetases progressively added new domains in an accretive way. These domains are dispensable for the function in protein synthesis. Unexpectedly, the fecundity of these architectural decorations appears to be unmatched by any other protein family. New functions emanate from these decorations, and are captured by the more than 200 natural splice variants, many of which are repurposed by ablating the catalytic domain while retaining the novel ones. These finding have led to the implementation of many applications for disease intervention.