Peroxisome-Proliferating Activating Receptors (PPARs) have long been established as validated targets for therapeutic intervention in several important disease states, including type II diabetes and dyslipidemia. More recently, evidence has implicated novel regulatory roles for PPARs in cancer, inflammation and neurodegeneration. Although current PPAR targeting treatments exist, most are associated with undesirable and potentially life-threatening side effects. Consequent from these observations is a significant research effort into PPAR modulator drug discovery and design. In this review, the progress of PPAR modulator design over the past several years will be highlighted. Particular focus on how detailed structural information and virtual screening techniques can aid in the rational design and development of tailored next generation PPAR drug therapeutics will be discussed.