In Saccharomyces cerevisiae the histone H2A variant H2A.Z replaces H2A in about 10% of nucleosomes. H2A.Z is involved in all DNA-templated processes including transcriptional regulation. H2A.Z is found in nucleosomes flanking the nucleosome free region of promoters. While deletion of HTZ1 in S. cerevisiae leads to rapamycin sensitivity, the molecular mechanism behind this sensitivity is not well understood. Here we show that rapamycin sensitivity is yeast strain-specific. When treated with rapamycin, the htz1D strain is unable to properly express several genes found in Target Of Rapamycin protein complexes as well as genes whose expression are critical for amino acid uptake by yeast, including GAP1 and GTR1. We also find an epistatic relationship between HTZ1 and GTR1 (whose protein product is a member of the exit from rapamycin-induced growth arrest complex and a GTPase that is required for the proper activation of the Tor1 kinase. Although GTR1 is normally upregulated in the presence of rapamycin, overexpression of GTR1 does not rescue the sensitivity phenotype seen in the htz1D strain. Additionally, the phosphorylation of downstream targets of the protein kinase A is affected in the htz1D strain. Gene expression defects, coupled with disrupted protein kinase A signaling pathway combine to make the htz1D strain sensitive to rapamycin. Our study has identified a novel role for histone H2A.Z in regulating both the TOR and PKA signal pathways.