Methylation of lysine 36 on histone H3 (H3K36) is catalyzed by the Set2 methyltransferase and is linked to transcriptional regulation. Previous studies have shown that trimethylation of H3K36 by Set2 is directed through its association with the phosphorylated repeats of the RNA polymerase C-terminal domain (RNAPII CTD). Here, we show that disruption of this interaction through the use of yeast mutants defective in CTD phosphorylation at serine 2 results in a destabilization of Set2 protein levels and H3K36 methylation. Consistent with this, we find that Set2 has a short half-life and is co-regulated, with RNAPII CTD phosphorylation levels, during logarithmic growth in yeast. To probe the functional consequence of uncoupling Set2-RNAPII regulation, we expressed a truncated and more stable form of Set2 that is capable of dimethylation but not trimethylation in vivo. Results of high throughput synthetic genetic analyses show that this Set2 variant has distinct genetics from either SET2 or set2Δ and is synthetically sick or lethal with a number of transcription elongation mutants. Collectively, these results provide molecular insight into the regulation of Set2 protein levels that influence H3K36 methylation states.