Heterochromatin protein 1 (HP1) is an epigenetic gene silencing protein that is regulated by lysine 9 methylation of histone H3. Most eukaryotes have at least three HP1 homologs with similar domain structures but with different localization patterns and functions in heterochromatin and euchromatin. However, little is known about the genome-wide effects of the three main HP1 homologs on gene expression. Here, to gain insight into the different gene expression effects of the three HP1 homologs, we performed a comprehensive and comparative microarray analysis of Drosophila HP1 homologs. Bioinformatic analysis of the microarray profiling revealed significant similarity and uniqueness in the genes altered in HP1-knockdown S2 cells in Drosophila. Although global changes of these transcripts were surprisingly subtle (4-6%), there were ~582 common target genes for the three HP1s that showed transcript levels either reduced or induced >1.5-fold. Depletion of HP1 resulted in up-regulated and down-regulated gene profiles, indicating that HP1 mediates both repression and activation of gene expression. This study is the first to systematically analyze the bioinformatics of HP1 paralogs and provide basic clues to the molecular mechanism by which HP1 might control gene expression in a homolog-specific manner.