Thirty-nine of the 44 chicken HI and core histone genes are located in a major histone gene cluster of 110 kb, the others residing in four separate regions. The 42 sequenced genes encode a set of HI and core histone amino acid sequences, as follows: six HI, three H2A, four H2B and two H3 variants, and an H4 protein. We generated and analyzed systematically a series of chicken DT40 mutants, which are, respectively, devoid of one or more histone genes, using gene targeting techniques. All of histone gene families HI, H2A, H2B, H3 and H4 possess the inherent ability to compensate for the deletion or inactivation of one or two particular members. One allele of the major histone gene cluster is enough for proliferation of the chicken DT40 B cell line. Only one of the 12 HI gene copies is enough for the proliferation of DT40 cells. HI and core histone variants are involved in regulation of the expression of specific genes, and this individual participation is not compensated for by any residual variant of the same subtype(s).