In eukaryotes, DNA is assembled with histones to form nucleosomes, the basic subunit of chromatin structure. The wrapping of DNA around histone octamers to form nucleosomal filaments and further folding of these filaments are necessary to contain eukaryotic genomes within nuclei. However, the dense packing of chromatin in nuclei and the association of DNA with histones restrict the access of proteins involved in gene transcription to DNA. Abundant biochemical data supports a long-standing correlation between histone acetylation and gene activation, suggesting that histone acetylation acts to enhance the access of transcription-associated proteins to DNA. However, despite this correlation, nuclear enzymes responsible for transcription-associated histone acetylation have been identified only recently. Here we review evidence suggesting that histone acetylation represents a major pathway for transcriptional regulation, and discuss possible roles for transcription-associated histone acetyltransferases in this regulation.