landmark descriptions of the genomes of several model organisms. The significance of these findings becomes even greater following the nearly full sequence assembly of the human genome. Together, these “genome projects” have shown that more complex eukaryotic model organisms have a much bigger genome than unicellular eukaryotes, although the increased “biocomplexity” is not reflected by an equivalent expansion in the number of protein-coding genes (e.g., ~40,000 in humans vs. ~6,000 in Saccharomyces cerevisiae). These results strongly suggest that biocomplexity is only in part regulated by overall gene number, but largely depends on combinatorial control triggering a vast number of gene expression patterns. In addition, mechanisms other than DNA sequence information have been used during evolution to better index and regulate the complex developmental programs and key regulatory processes, such as chromosome segregation and cell division of eukaryotic genomes. In the nuclei of almost all eukaryotic cells, genomic DNA is highly folded and compacted with histone and nonhistone proteins in a dynamic polymer called chromatin. The discoveries that DNA methylation, nucleosome remodeling, histone modification, and noncoding RNAs can organize chromatin into accessible (“euchromatic”) and inaccessible (“heterochromatic”) subdomains reveal epigenetic mechanisms that considerably extend the information potential of the genetic code. Thus, one genome can generate many “epigenomes” (Fig. 1), as the fertilized egg progresses through development and translates its information into a multitude of cell fates. These epigenetic mechanisms are crucial for the function of most, if not all, chromatin-templated processes and link alterations in chromatin structure to allele-specific expression differences, developmental programming of cell lineages, chromosome segregation, DNA repair, and genome stability. The implications of epigenetic research for human biology and disease, including cancer and aging, are far reaching. The basic repeating unit of chromatin is the nucleosome, consisting of 147 bp of DNA wrapped around an octamer of the core histones H2A, H2B, H3, and H4 (Luger et al. 1997). Posttranslational modifications of the protruding histone amino-termini (histone “tails”) were proposed 40 years ago to affect gene expression (Allfrey et al. 1964) and have since been demonstrated as important modulators of chromatin structure, culminating in the “histone code” hypothesis (Strahl and Allis 2000; Turner 2000; Jenuwein and Allis 2001). Histone modifications include acetylation, phosphorylation, methylation (arginine and lysine), ubiquitination, and ADP ribosylation (van Holde 1988). In the last 4 years, histone lysine methylation has emerged as a central epigenetic modification (Jenuwein 2001; Zhang and Trilogies of Histone Lysine Methylation as Epigenetic Landmarks of the Eukaryotic Genome