The complete nucleotide sequence of four human histone genes has been determined. Each gene codes for a core histone protein which is very homologous with the corresponding calf thymus of rat histones. The 5' and 3' flanking regions of the human histone genes contain previously identified concensus sequences: the TATA box, the GACTTC element; the CCAAT sequence; the 3' terminal dyad symmetry element thought to be involved in transcription termination; and a recently identified H2b specific upstream sequence. A putative H2a specific upstream sequence 5'-TTCTTGGACTCCTCTTTTC-3' is present approximately 40 base pairs upstream from the TATA box in the human H2a gene promoter. Nuclease S1 analysis of the human histone mRNAs encoded within each of these clones demonstrates that the mRNA terminii map to the expected positions relative to the known concensus sequences, and that the abundance of each mRNA is regulated during the HeLa cell cycle. Finally, in contrast to the H2b, H3 and H4 mRNAs encoded within clones pHh 4A/pHh4C, pHh5B and pHu4A, respectively, the H2a mRNA encoded by Hh5G is not present in human placental RNA.