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 δ-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 swi4Δ, mbp1Δ, and swi6Δ mutants with respect to histone gene transcription and for interactions with spt10Δ and spt21Δ. Our results suggest that MBF and SBF play only modest roles in activation of histone gene transcription. In addition, we were surprised to find that swi4Δ, mbp1Δ, and swi6Δ mutations suppress the spt21Δ Spt− phenotype, but not the spt21Δ defect in histone gene transcription. In contrast, both swi4Δ and mbp1Δ cause lethality when combined with spt10Δ. To learn more about mutations that can suppress the spt21Δ Spt− phenotype, we performed a genetic screen and identified spt21Δ suppressors in seven additional genes. Three of these spt21Δ suppressors also cause lethality when combined with spt10Δ. Analysis of one spt21Δ suppressor, reg1, led to the finding that hyperactivation of Snf1 kinase, as caused by reg1Δ, suppresses the Spt− phenotype of spt21Δ. Taken together, these genetic interactions suggest distinct roles for Spt21 and Spt10 in vivo that are sensitive to multiple perturbations in transcription networks.