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 delta-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 swi4Delta, mbp1Delta, and swi6Delta mutants with respect to histone gene transcription and for interactions with spt10Delta and spt21Delta. 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 swi4Delta, mbp1Delta, and swi6Delta mutations suppress the spt21Delta Spt(-) phenotype, but not the spt21Delta defect in histone gene transcription. In contrast, both swi4Delta and mbp1Delta cause lethality when combined with spt10Delta. To learn more about mutations that can suppress the spt21Delta Spt(-) phenotype, we performed a genetic screen and identified spt21Delta suppressors in seven additional genes. Three of these spt21Delta suppressors also cause lethality when combined with spt10Delta. Analysis of one spt21Delta suppressor, reg1, led to the finding that hyperactivation of Snf1 kinase, as caused by reg1Delta, suppresses the Spt(-) phenotype of spt21Delta. Taken together, these genetic interactions suggest distinct roles for Spt21 and Spt10 in vivo that are sensitive to multiple perturbations in transcription networks.