A large number of studies have indicated that thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone inhibit tumor growth, progression, and metastasis. These agents are specific agonists for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) but also engage other pathways. In lung cancer, these agents have been shown to induce apoptosis and inhibit tumor growth in xenograft models. Retrospective studies have indicated a significant decrease in lung cancer risk in patients using these agents, suggesting that TZDs may be chemopreventive for lung cancer. However, emerging data suggest that chronic use of these agents is associated with increased risk of adverse cardiovascular events. It is therefore critical to determine the relative contributions of PPAR gamma-dependent versus PPAR gamma-independent pathways in mediating both the anti-tumorigenic effects and the cardiovascular effects of TZDs. This review examines these pathways with a specific focus on the role of TZDs and PPAR gamma in lung cancer.