Histone amino termini are post-translationally modified by both transcriptional coactivators and corepressors, but the extent to which the relevant histone modifications contribute to gene expression, and the mechanisms by which they do so, are incompletely understood. To address this issue, we have examined the contributions of the histone H3 and H4 amino termini, and of the coactivator and histone acetyltransferase Gcn5p, to activation of a small group of Gcn4p-activated genes. The histone H3 tail exerts a modest (about 2-fold) but significant effect on activation that correlates with a requirement for Gcn5p and is distributed over multiple lysine residues. The H4 tail also plays a positive role in activation of some of those genes tested, but this does not correlate as closely with Gcn5p coactivation. Microarray experiments did not reveal a close correspondence between those genes activated by Gcn4p and genes requiring the H3 or H4 tail, and analysis of published microarray data indicates that Gcn4p-regulated genes are not in general strongly dependent on Gcn5p. However, a large fraction of genes activated by Gcn4p were found to be repressed by the H3 and H4 amino termini under non-inducing conditions, indicating that one role for Gcn4p is to overcome repression mediated by the histone tails.