In this issue of Blood, Nair et al report on a computationally derived hepatocyte-specific cis-regulatory module (HS-CRM8) to accomplish high tissue-specific expression in gene therapy for hemophilia. When HS-CRM8 is introduced upstream of a minimal liver-specific promoter in an adenoassociated virus (AAV) that expresses a codon-optimized hyperactive human factor IX (FIX) mutant (FIX Padua), it provides a >1 log increase in systemic FIX protein levels and supraphysiological activity over a range of vector doses.