Previous studies comparing the effects of two histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) and CG-1521, have shown that these compounds selectively inhibit HDAC and induce differentially acetylated p53 isoforms and assembly of mutually exclusive transcriptional complexes on the p21 promoter. To determine whether the differential transcriptional regulation seen in p21 gene is unique or whether it is representative of the genome-wide effects of these two HDAC inhibitors, we have used microarray and Ingenuity pathway analysis to compare the effects of TSA and CG-1521 on gene expression on LNCaP cells. Gene array analysis confirmed by quantitative real-time PCR shows that CG-1521 modulates the expression of a highly circumscribed group of genes involved in cell cycle progression and cell death. In contrast, TSA appears to induce widespread transrepression of many genes and does not modulate the expression of the same cohort as CG-1521. These data show that the selective effects of CG-1521 and TSA on the assembly of transcription complexes are not unique to the p21 gene and suggest that selective inhibition of HDAC can lead to significant changes in gene expression through the acetylation of transcription factors including but not limited to p53.