Increased production of the pro-inflammatory enzyme cyclooxygenase-2 (Cox-2) and altered expression and activity of peroxisome proliferator-activated receptor γ (PPARγ) have been observed in many malignancies. Both the PPARγ ligands and the Cox-2 inhibitors possess anti-inflammatory and anti-neoplastic effects in vitro and have been assessed for their therapeutic potential in several pre-clinical and clinical studies. Recently, multiple interactions between PPARγ and Cox-2 signaling pathways have been revealed. Understanding of the cross-talk between PPARγ and Cox-2 might provide important novel strategies for the effective treatment and/or prevention of cancer. This article summarizes recent achievements involving the functional interactions between the PPARγ and Cox-2 signaling pathways and discusses the implications of such interplay for clinical use.