The cell cycle protein cyclin D1 plays a critical role in controlling the G1/S transition via its ability to regulate the activity of multiple cyclin-dependent kinases (CDKs). The transcriptional regulation of the cyclin D1 gene is well understood, and several studies have indicated that cyclin D1 translation is decreased upon activation of the eIF2a kinases. We examined the effect of activation of the eIF2a kinases PKR and PERK on cyclin D1 protein levels and translation, and determined that cyclin D1 protein levels decrease upon the induction of PKR and PERK catalytic activity, but that this decrease is not due to translation. Inhibition of the 26S proteasome with MG132 rescued cyclin D1 protein levels, indicating that rather than inhibiting translation, PKR and PERK are acting to increase cyclin D1 degradation. Interestingly, this effect still requires eIF2a phosphorylation at serine 51, as cyclin D1 remains unaffected in cells containing a non-phosphorylatable form of the protein. This proteasome-dependent degradation of cyclin D1 requires an intact ubiquitination pathway, although the ubiquitination of cyclin D1 is not itself affected. Furthermore, this degradation is independent of phosphorylation of cyclin D1 at threonine 286, which is mediated by the glycogen synthase kinase 3ß (GSK-3ß) and mitogen activated protein kinase (MAPK) pathways as described in previous studies. Our study reveals a novel functional cross-talk between the eIF2a phosphorylation and the proteasomal degradation of cyclin D1, and that this degradation is dependent upon eIF2a phosphorylation during short, but not prolonged periods of stress.