Glucocorticoids (GC) are essential to maintain normal life. They are important for the healthy development of the unborn and also in adult human to confront physiological life stress. But, when GC rise over physiological concentrations for a long period of time, the Central Nervous System (CNS) is predisposed to develop psychiatric disorders and neurological diseases. GC deleterious effects in the CNS are partially mediated through the activation of constitutive nitric oxide synthase (cNOS). This GC effect leads to a strong involvement with the nitric oxide pathway (NO-pathway) and reactive oxygen species (ROS) derivates. Besides this, supporting evidence of D-Arginine (D-Arg) neuroprotective actions against neurotoxicity induced by high levels of GC in the CNS will be discussed in this study. Noteworthy, D-Arg does not interfere with GC immune-suppressive and anti-inflammatory effects. These observations suggest a novel way to neutralize GC neurotoxic effects in the CNS without compromising their desirable peripheral actions.