Peroxisome proliferator-activated receptor-gamma (PPARγ) is a ligand-activated transcription factor of the nuclear receptor superfamily that regulates genes involved in differentiation, metabolism and immunity. PPARγ-ligands are used for therapy of type 2 diabetes and hold the promise for treatment of inflammation and cancer. As a central regulatory component, PPARγ activity is well regulated during various cellular processes, and indeed mitogenic stimulation often suppresses PPARγ’s genomic activity. This down-regulation is mediated largely by the extracellular signal-regulated kinase 1/2 (ERKs)/mitogen-activated protein kinases (MAPKs) signaling cascade, which attenuates PPARγ’s transactivation function either by an inhibitory phosphorylation or by modulating PPARγ’s nucleo-cytoplasmic compartmentalization. The latter is achieved by the mitogen-induced nuclear export of PPARγ through its direct interaction with the ERK cascade component MAPK/ERK-kinases 1/2 (MEKs). Upon mitogenic stimulation, MEKs translocate into the nucleus, but are rapidly exported from this location by their N-terminal nuclear export signal (NES), in a process that is accompanied by the export of their interacting nuclear PPARγ molecules. Interestingly, it was recently demonstrated that PPARγ has cytoplasmatic activities, and therefore, the MEK-dependent shuttle may also represent a mechanism for control of the extra-nuclear/non-genomic actions of PPARγ. Because of the similarity within nuclear receptor docking motifs, it is possible that the same mechanism may control the nuclear and cytoplasmatic activity of other receptors. The changes in the subcellular localization of PPARγ may also represent novel targets for selective interference in patients with chronic inflammatory or proliferation-related diseases.