Genes placed near telomeres in S. cerevisiae succumb to position-effect variegation. SIR2, SlR3, SIR4, NATl, ARD7, and HHF2 (histone H4) were identified as modifiers of the position effect at telomeres, since banscrip tional repression near telomeres was no longer observed when any of the modifier genes were mutated. These genes, in addition to SIRT, have previously been shown to repress transcription at the silent mating loci, HML and HMR. However, there were differences between transcriptional silencing at telomeres and the HM loci, as demonstrated by suppressor analysis and the lack of involvement of S/RI in telomeric silencing. These findings provide insights into telomeric structure and function that are likely to apply to many eukaryotes. In addition, the distinctions between telomeres and the HM loci suggest a hierarchy of chromosomal silencing in S. cerevisiae.