The use of histone deacetylase (HDAC) inhibitors has revealed an essential role for deacetylation in transcription of IFN-responsive genes. The HDAC1 protein associates with both signal transducer and activator of transcription (STAT) 1 and STAT2, and IFN-alpha stimulation induces deacetylation of histone H4. Inhibition of HDAC1 by small interfering RNA (siRNA) decreases IFN-alpha responsiveness whereas expression of HDAC1 augments the IFN-alpha response, demonstrating that HDAC1 modulates IFN-alpha-induced transcription. Importantly, the innate antiviral response is inhibited in the absence of deacetylase activity. The requirement for deacetylase is shared by IFN-gamma transcription response and may represent a general requirement for STAT-dependent gene expression.