The very long DNA of the eukaryotic cells must remain functional when packaged into the cell nucleus. Although we know very little about this process, it is clear at this time that chromatin and its post-translational modifications play a pivotal role. Yeast Saccharomyces cerevisiae provides a powerful genetic and biochemical model system for deciphering the molecular machinery involved in chromatin modification and transcriptional regulation. In this chapter, we describe a novel method, the Global Proteomic analysis in S. cerevisiae (GPS), for the global analysis of the molecular machinery required for proper histone modifications. Since many of the molecular machineries involved in chromatin biology are highly conserved from yeast to humans, GPS has proven to be an outstanding method for the identification of the molecular pathways involved in chromatin modifications.