Abstract: Mutations in SPT10 and SPT21 of Saccharomyces cerevisiae have been previously shown to cause two prominent mutant phenotypes: (1) defects in transcription of particular histone genes and (2) suppression of Ty and d insertion mutations (Spt- phenotype). The requirement for Spt10 and Spt21 for transcription of particular histone genes suggested that they may interact with two factors previously shown to be present at histone loci, SBF (Swi4 and Swi6) and MBF (Mbp1 and Swi6). Therefore, we have studied swi4D, mbp1D, and swi6D mutants with respect to histone gene transcription and for interactions with spt10D and spt21D. Our results suggest that MBF and SBF play only modest roles in activation of histone gene transcription. In addition, we surprisingly found that swi4D, mbp1D, and swi6D mutations suppress the spt21D Spt- phenotype, but not the spt21D defect in histone gene transcription. In contrast, both swi4D and mbp1D cause lethality when combined with spt10D. To learn more about mutations that can suppress the spt21D Spt- phenotype, we performed a genetic screen and identified spt21D suppressors in seven additional genes. Three of these spt21D suppressors also cause lethality when combined with spt10D. Analysis of one spt21D suppressor, reg1, led to the finding that hyperactivation of Snf1 kinase, as caused by reg1D , suppresses the Spt- phenotype of spt21D. Taken together, these genetic interactions suggest distinct roles for Spt21 and Spt10 in vivo that are sensitive to multiple perturbations in transcription networks.