A dysregulated response of the neuroimmune system is a main contributor to the progression of neurodegeneration in Parkinson's disease (PD). Recent findings suggest that protracted activating stimuli including α-synuclein, drive microglia to acquire maladaptive functions and to assume a harmful phenotype that prevail over a restorative one. Based on this concept, disease-modifying drugs should be aimed at targeting suppression of harmful-activated microglia and the associated production of neurotoxic molecules as pro-inflammatory cytokines, while sparing or inducing beneficial-activated microglia. In this study, we review current evidence in support of the beneficial effect of targeting peroxisome-proliferator-activated receptor (PPAR)-γ to achieve neuroprotection in PD. PPAR-γ agonists as rosiglitazone and pioglitazone are currently gaining increasing attention as promising disease-modifying drugs in this disorder. Early in vitro studies, followed by studies in in vivo models of PD, have provided convincing evidence that these drugs inhibit neuronal degeneration likely by selectively targeting the expression of neurotoxic factors in reactive microglia. Potential therapeutic application has been corroborated by recent report of pioglitazone neuroprotective activity in a non-human primate model of PD. All together, preclinical evidence have prompted the translation of pioglitazone to a phase II clinical trial in early PD.