Histones are subject to a complex and dynamic set of covalent modifications that are thought to be involved in the modulation of transcription during development, in X chromosome inactivation in female mammals, and in genome stability and meiotic chromosome dynamics. Histone modifications reported to date include acetylation, phosphorylation, methylation, ADP ribosylation, and ubiquitination (Fig. 1). Multiple residues on each of the four core histones have been identified as potential modification sites and some lysine side chains can be either methylated or acetylated. Given the number of sites and the variety of possible modifications, the combinatorial possibilities are extremely large and it is tempting to believe that histone modification has a regulatory role. This led to the histone code hypothesis, which postulated that these modifications may be interdependent and that they may culminate in specific histone landscapes that provide entry sites for proteins responsible for higher order chromatin organization and gene activation or inactivation (Strahl and Allis 2000; Jenuwein and Allis 2001). Provided that patterns of histone modifications are subject to mitotic inheritance, their net effect will be an increase in the information content of the genome. However, the complexity of the process and the fact that chromatin structure remains poorly defined (except when presented as candy-colored PowerPoint cartoons) has hidden the real nature of the impact of histone modifications on the structure and regulated expression of the genome, and the magnitude of the effects exerted by different histone modifications has been difficult to assess from biochemical data. The lack of a candidate mechanism that could mediate clonal transmission of patterns of histone modifications has also been a problem. Surprising recent data indicate that the nucleosome does not merely serve as an armature for informational posttranslational modification, but rather that the act of transcription causes the introduction of a histone H3 variant (H3. 3) that attracts activating histone modifications and directly participates in the assembly of chromatin configurations favorable for transcription (Ahmad and Henikoff 2002). Although important questions remain to be answered, recent progress in the genetic analysis of histone modification has provided a new foundation for chromatin biology.