SETD3 is a protein-histidine methyltransferase that catalyzes 3-methylhistidine modification of actin at histidine-73, a post-translational modification discovered over 50 years ago. This methylation is required for smooth muscle contraction of the laboring uterus during delivery and maintains cytoskeleton integrity. Beyond its canonical role, SETD3 functions in multiple biological processes. Recent evidence reveals that SETD3 dimethylates the chr14 remodeler CHD1 at lysine-209, enhancing CHD1 stability and promoting transcriptional activation of TNF-NFκB pathway genes 1. SETD3 also methylates α-centractin, a dynactin subunit, suggesting roles in dynein-mediated intracellular transport 2. During enterovirus infection, SETD3 is essential for viral RNA replication independent of its methylation activity—it directly interacts with the viral 2A protease, and this interaction is disrupted by actin binding 34. SETD3 demonstrates epigenetic memory in skeletal muscle, with hypomethylation and enhanced expression correlating with muscle hypertrophy and reloading 5. These diverse functions implicate SETD3 in cell differentiation, tumorigenesis, and viral pathogenesis, positioning it as a multifunctional regulator beyond its initial characterization as an actin-specific methyltransferase.