The regulation of chromatin structure is essential to life. In eukaryotic organisms, several classes of protein exist that can modify chromatin structure either through ATP-dependent remodeling or through the post-translational modification of histone proteins. A vast array of processes ranging from transcriptional regulation to DNA repair rely on these histone-modifying enzymes. In the last few years, enzymes involved in the post-translational modification of histone proteins have become a topic of intense interest. Our work and the work of several other laboratories has focused largely on understanding the biological role of the yeast histone methyltransferase COMPASS (complex of proteins associated with Set1) and its human homologue the MLL complex. The Set1-containing complex COMPASS acts as the sole histone H3 lysine 4 methyltransferase in Saccharomyces cerevisiae, and this methyl mark is important for transcriptional regulation and silencing at the telomeres and rDNA loci. Another histone methyltransferase, Dot1, methylates lysine 79 of histone H3 and is also essential for proper silencing of genes near telomeres, the rDNA loci, and the mating type loci. Employing our global biochemical screen GPS (global proteomic analysis of S. cerevisiae) we have been successful in identifying and characterizing several key downstream and upstream regulators of both COMPASS and Dot1 histone methyltransferase activity. This review details efforts made towards understanding the regulatory mechanisms and biological significance of COMPASS and Dot1p-mediated histone methylation.