Tumor cells depend on and are able to modulate the tumor stroma establishing a permissive and supportive environment of their own. Targeting the tumor stroma has evolved as a novel concept that has attracted attention of cancer researchers aiming at the treatment of metastatic cancer. The novel paradigm is that modulating the stroma will possibly not cure the cancer, but will make it a manageable disease for long periods of time by prohibiting the cancer from growing beyond a certain mass. Accordingly, in the last years, a multitude of stroma-targeting agents were developed comprising either classic small molecule drugs (e.g. sorafenib, an inhibitor of multiple tyrosine kinases) or recombinant antibodies (e.g. anti-VEGF) for targeting of tumor angiogenesis. Apart from these specifically targeted drugs, some well established drugs, primarily designed for non-oncologic diseases, have revealed antitumor activity on the basis of nuclear receptor modulation unfolding pleiotropic biological effects including stroma modulation. Peroxisome Proliferator Activated Receptor (PPAR) agonists, particularly thiazolidinedione derivatives such as pioglitazone and ciglitazone, are promising examples as they exert both a direct antitumoral and a broad spectrum of anti-stromal, antiangiogenic and immuno-modulating activities. This review will focus on the stroma-mediated anticancer activities of PPAR agonists.