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, PPAR? has been intensively evaluated as a target for anticancer therapy in preclinical models. However, PPAR? has been reported to act both as a promoter and suppressor of neoplasia, and the role of PPAR? 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. PPAR? has strong anti-inflammatory and anti-angiogenic effects, extending the repertoire of potential targets of PPAR? ligands beyond cell-autonomous mechanisms of cancer. The heterogeneous cellular targets and the biphasic effects of PPAR? on various pro and anti-tumor processes may account for the apparent paradoxical effects of PPAR? agonists. Here we review the action of PPAR? agonists on angiogenesis and inflammation in the context of tumorigenesis as an integrated tissue process and discuss potential explanations for the conflicting effects of PPAR? 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 PPAR?. This will be paramount if the potent biological activity of PPAR? agonists are to be harnessed for cancer therapy.