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Upon glucose starvation, S. cerevisiae shows a dramatic alteration in transcription, resulting in wide-scale repression of most genes and activation of some others. This coincides with an arrest of cellular proliferation. A subset of such cells enters quiescence, a reversible non-dividing state. Here, we demonstrate that the conserved transcriptional corepressor Tup1 is critical for transcriptional repression after glucose depletion. We show that Tup1-Ssn6 binds new targets upon glucose depletion, where it remains as the cells enter the G0 phase of the cell cycle. In addition, we show that Tup1 represses a variety of glucose metabolism and transport genes. We explored how Tup1 mediated repression is accomplished and demonstrated that Tup1 coordinates with the Rpd3L complex to deacetylate H3K23. We found that Tup1 coordinates with Isw2 to affect nucleosome positions at glucose transporter HXT family genes during G0. Finally, microscopy revealed that a quarter of cells with a Tup1 deletion contain multiple DAPI puncta. Taken together, these findings demonstrate the role of Tup1 in transcriptional reprogramming in response to environmental cues leading to the quiescent state. Author summary: Quiescence is a very common and important state for the cells of many organisms, where cell functions 'pause' but can resume when the right conditions are met. Most microbes exist in a quiescent state and will start growing and dividing again in the presence of nutrients or other cues. In mammals, a quiescent state is used to maintain stem cell populations and cancer cells often evade treatment by entering quiescence. The budding yeast Saccharomyces cerevisiae is an excellent model for studying quiescence because we can easily isolate populations of quiescent cells. Since budding yeast share many proteins and cellular pathways with higher organisms, our findings are applicable to more complex systems, which may be relevant to maintenance of healthy cells or provide insight to treating disease states. We know that a hallmark of quiescence is reduced transcription, and we are interested in how this change occurs. We have examined how the protein Tup1 causes changes in gene expression in cellular quiescence. We also looked at how Tup1-dependent changes depend on other chromatin interacting factors, such as the histone deacetylase Rpd3, the transcription factor Xbp1, or the chromatin remodeling protein Isw2. [ABSTRACT FROM AUTHOR]