Abstract: Asf1 is a conserved histone H3/H4 chaperone that can assemble and disassemble nucleosomes, and promote histone acetylation. Set2 is an H3 K36 methyltransferase. The functions of these proteins intersect in the context of transcription elongation by RNA polymerase II: both contribute to the establishment of repressive chromatin structures which inhibit spurious intragenic transcription. Here we characterize further interactions between budding yeast Asf1 and Set2 using assays of intragenic transcription, H3/H4 post-translational modification, coding region cross-linking of Asf1 and Set2, and co-occurrence of Asf1 and Set2 in protein complexes. We find that at some genes Asf1 and Set2 control chromatin metabolism as components of separate pathways. However the existence of a low abundance complex containing both proteins suggests that Asf1 and Set2 can more directly collaborate in chromatin regulation. Consistent with this possibility, we show that Asf1 stimulates Set2 occupancy of the coding region of a highly transcribed gene by a mechanism that depends on Asf1 binding to H3/H4. This function of Asf1 promotes the switch from di- to trimethylation of H3 K36 at that gene. These results support the view that Set2 function in chromatin metabolism can intimately involve histone chaperone Asf1.