Protein histidine (His) phosphorylation and responsible His kinases (HKs) have been well characterized in bacteria (two-component systems; TCSs), while little is known about the HKs in eukaryotic cells. Although eukaryotic HK activities towards histone H4 has been reported over 40 years ago, with their potential involvement in cell proliferation, the identity of the kinase remains elusive. Here we report our progress towards the isolation and identification of HKs using chemical biology tools