To elucidate the manner in which histones and nonhistone chromosomal proteins interact to render histone genes transcribable in HeLa S3 cells, we have examined transcription of histone mRNA sequences from DNA, as well as from several DNA-chromosomal protein complexes. Histone mRNA sequences were assayed by hybridization to a 3H-labeled single-stranded DNA complementary to histone mRNAs. Our results indicate that DNA is an effective template for transcription of histone mRNA sequences and that histones by themselves inhibit transcription from DNA, including transcription of histone genes, in a dose-dependent, nonspecific manner. When complexed with DNA alone, nonhistone chromosomal proteins do not affect the transcription of histone mRNA sequences. However, when associated with DNA in the presence of histones, nonhistone chromosomal proteins are capable of selectively rendering histone genes transcribable. These results suggest a possible role for nonhistone chromosomal proteins in mediating the interactions of histones with DNA to render histone genes transcribable.