The ubiquitin gene is prone to duplications and insertions, leading to the formation of new fusion proteins [52, 53] . ISG15 likely emerged approximately 400-600 million years ago, when a nucleotide stretch from the polyubiquitin precursor gene, encoding a ubiquitin-dimer, was accidentally inserted in an area of the genome that was or that came under control of an interferon promoter. From an agnostic point of view, one could argue that ISG15 simply has no relevant function. The moderate or absent phenotype of the ISG15 knockout in mice [11] , the fact that ISG15 has not (yet) established its very own family of conjugating and deconjugating enzymes, and ISG15's relatively low degree of conservation between species would all support this view. Yet, ISG15's massive expression upon interferon challenge [54] likely reflects a role in anti-microbial or anti-viral defense [55] [56] [57] [58] [59] . And adaptation to the specific needs of host immunity often demands polymorphism. As a result, some genes most critical to the immune response are paradoxically least conserved. For example, cytokines and cytokine receptors substantially differ between species [60] and it is interesting to note that ISG15 and ubiquitin were initially reported to be cytokines [61, 62] . Similar observations were made for the ubiquitin-like modifier FUBI (also known as Fau or MNSFb) [63, 64] . If true, how do these factors gain access to the secretory pathway? It may pay to approach ISG15 from a less conventional perspective and from this vantage point, we might uncover new functions of ubiquitin as well.