Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with pleiotropic effects on cell fate and metabolism. Because of its anti-proliferative, pro-apoptotic and differentiation promoting activities, PPARgamma has been intensively evaluated as a target for anti-cancer therapy in preclinical models. However, PPARgamma has been reported to act both as a promoter and suppressor of neoplasia, and the role of PPARgamma activating ligands as well as antagonists in therapy remains controversial. In the past decade a new picture of tumors as a disease that involves changes in the non-cancerous tumor bed, including angiogenesis, inflammation and other stromal changes has emerged. PPARgamma has strong anti-inflammatory and anti-angiogenic effects, extending the repertoire of potential targets of PPARgamma ligands beyond cell autonomous mechanisms of cancer. The heterogeneous cellular targets and the biphasic effects of PPARgamma on various pro and anti-tumor processes may account for the apparent paradoxical effects of PPARgamma agonists. Here we review the action of PPARgamma agonists on angiogenesis and inflammation in the context of tumorigenesis as an integrated tissue process and discuss potential explanations for the conflicting effects of PPARgamma agonists on tumor progression and metastasis. Sorting out the various modes of action and defining their relative contribution in the context of tumor and host tissue as a heterogeneous target will therefore be crucial to understand the multi facetted effects of PPARgamma. This will be paramount if the potent biological activity of PPARgamma agonists are to be harnessed for cancer therapy.