Dosage compensation solves the chromosomal imbalance that is a result of sexual determination by sex chromosomes. It equalizes gene expression between the homogametic (XX) and heterogametic (XY) sexes and thus needs to selectively modify expression from the X chromosome in a sex-specific manner without affecting transcription on the autosomes. Various strategies have evolved in different organisms to achieve this balance, and their study has contributed significantly to our understanding of transcriptional gene regulation of whole chromosomes and established several paradigms of epigenetic control (Lucchesi 1998; Stuckenholz et al. 1999; Akhtar 2003). In mammals, dosage compensation is accomplished by inactivating one copy of the X chromosome in females via an epigenetic process of allele-specific modification of chromatin and DNA. In Drosophila, dosage compensation is achieved not by repression but by increasing the transcription specifically on the single male X chromosome (Hamada et al. 2005; Straub et al. 2005). Genetic screens for male-specific lethality (MSL) identified five protein-coding genes that are required for dosage compensation: Msl 1-3, male absent on the first (mof), and maleless (mle). Subsequent biochemical characterizations suggested that these proteins, together with two noncoding RNAs (roX1 and roX2), form what has been termed the dosage compensation complex (DCC) (for review, see Bashaw and Baker 1996; Gilfillan et al. 2004). Complex formation only occurs in males, as translation of the MSL-2 protein is inhibited in females. A first evidence for chromatin as a target in dosage compensation came from the observation of higher levels of histone H4K16 acetylation on the hyperactivated X detected by immunostaining (Turner et al. 1992). One of the msl genes, MOF, is a histone acetyl-transferase (HAT) that acetylates H4 at Lys 16 and is able to cause derepression of chromatinized templates in vitro and in vivo (Akhtar and Becker 2000). Thus, it appears that the HAT activity of MOF plays an important part in the mechanisms that lead to hyperactivation of the male X (Smith et al. 2000). A large body of work in different systems established that histone hyperacetylation correlates with gene activation, making this a feasible model (Wade et al. 1997). Yet how does the recruitment of a HAT activity that acetylates a single lysine on H4 result in a precise twofold up-regulation of mRNA? As histone acetylation is involved in promoter activation, it has been assumed that DCC is recruited to promoters of genes at the X chromosome, but is this really the site of action in vivo? Are individual genes targeted by DCC, or are large chromosomal regions covered? Equally as important, how does this process ensure regulation of X-linked genes that are dynamically expressed during development? Is compensation set up early in development for all genes independent of their subsequent activity, or is the DCC relocated dynamically to any activated gene? Many of these questions can be approached by defining sites and kinetics of DCC recruitment on the X chromosome in high spatial resolution at different developmental time points. No less than three reports in this issue of Genes & Development provide such chromosome-wide analysis of several MSL proteins. Together they provide important and unexpected insights into the process of dosage compensation, challenging and helping to redefine current models (Alekseyenko et al. 2006; Gilfillan et al. 2006; Legube et al. 2006).