Oxidative stress is a pathological feature common to a multitude of neurological diseases. The production of reactive oxygen species (ROS) is the main mechanism underlying this cellular redox imbalance. Antioxidants protect biological targets against ROS, therefore, they have been considered as attractive potential therapeutic agents to counteract ROS-mediated neuronal damage. However, despite encouraging in vitro and preclinical in vivo data, the clinical efficacy of antioxidant treatment strategies is marginal and most clinical trials using antioxidants as therapeutic agents in neurodegenerative diseases have yielded disappointing outcomes. This might in part be due to the need of adjustment in concentrations and time parameters between preclinical studies and clinical settings. Moreover new efficient delivery methods need to be investigated, particularly taking into account that a successful therapeutic agent for neurological diseases should readily cross the blood-brain barrier (BBB). In that sense, the use of compounds that cross the BBB and boost the endogenous antioxidant defense machinery, by activating for instance the Nrf2 pathway, or compounds that are able to modulate ROS production, such as NOX enzyme inhibitors, seems to represent a more promising approach to combat oxidative stress in the CNS. Here we present a brief overview of the main players in oxidative stress and outline evidences of their involvement in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and multiple sclerosis. Finally, we review and critically discuss the potential of antioxidants as therapeutics for central nervous system disorders with a special focus on emerging novel therapeutic strategies.