Although targeting ISG15, USP18, and UBE2L6 has the potential to alleviate hypertension, T2DM, and age-associated cardiomyopathies, we are still a long way from understanding the specific consequences of ISGylation on validated substrates (Zhao et al., 2005) and how ISGylation is regulated in a context-specific manner, knowledge that will be essential for the development of ISGylation-targeted therapies. This evidence concerns the gene USP18 and type 2 diabetes mellitus.