Abstract: Chromatin structure exerts vital control over gene expression, DNA replication, recombination, and repair. In addition to altering RNA polymerase II's (Pol II) accessibility to DNA, histones are involved in the recruitment of activator and repressor complex(es) to regulate gene expression. Histone deacetylase Rpd3 exists in two distinct forms, Rpd3S and Rpd3L. Several recent studies demonstrated that the Eaf3 chromodomain, an Rpd3S subunit, recognizes Set2-methylated histone H3K36, initiating Rpd3 deacetylase activity in the wake of transcribing Pol II. Eaf3 and Set2 inhibit internal initiation within mRNA coding regions, similar to the transcription elongation factor and histone chaperone, FACT. Recent studies reviewed here demonstrate that histone deacetylation on the body of a transcribed gene is regulated via Set2-mediated methylation of histone H3-K36. These modifications provide restoration of normal chromatin structure in the wake of elongating Pol II and prevent inappropriate initiation within protein-coding regions masked by chromatin.