The physiological and pharmacological roles of peroxisome proliferator-activated receptor-beta (PPARbeta-also referred to as PPARdelta) are just beginning to emerge. It has recently become clear that PPARbeta has a function in epithelial tissues, but controversy exists due to inconsistencies in the literature. There is strong evidence that ligand activation of PPARbeta can induce terminal differentiation of keratinocytes, with a concomitant inhibition of cell proliferation. However, the role of PPARbeta in keratinocyte-specific apoptosis is less clear. Additionally, the role of PPARbeta in colonic epithelium remains unclear due to conflicting evidence suggesting that ligand activation of PPARbeta can potentiate, as well as attenuate, intestinal cancer. Recent studies revealed that ligand activation of PPARbeta can induce fatty acid catabolism in skeletal muscle and is associated with improved insulin sensitivity, attenuated weight gain and elevated HDL levels thus demonstrating promising potential for targeting PPARbeta for treating obesity, dyslipidemias and type 2 diabetes. Therefore, it becomes critical to determine the safety of PPARbeta ligands. This review focuses on recent literature describing the role of PPARbeta in epithelial tissues and highlights critical discrepancies that need to be resolved for a more comprehensive understanding of how this receptor modulates epithelial homeostasis.