Abstract: Asymmetric dimethylarginine (ADMA) and its enantiomer, symmetric dimethylarginine (SDMA), are naturally-occurring methylated metabolites of the L-arginine amino acid moiety of proteins followed by proteolysis (Grosse et al., 2020). These metabolites were first identified in human urine in 1970. At present, several other L-arginine metabolic products are known to occur naturally and invoke their distinct biological effects in health and disease. It is well established that both these metabolites, ADMA and SDMA, compete with L-arginine as a substrate of nitric oxide synthases (NOS). ADMA and SDMA inhibit and uncouple NOS, leading to the formation of superoxide (O2–) rather than nitric oxide (NO). Thus, these metabolites are linked to a dysregulated NO metabolome in neuronal/inflammatory cells, and this dysregulation is implicated in the neurodegeneration that follows brain trauma. Under pathological conditions, ADMA/SDMA is secreted and therefore found in excess in circulation and picked up by endothelial cells. In endothelial cells, ADMA uncouples endothelial NOS (eNOS). Uncoupled NOS enzymes produce superoxide, and normal NOS form NO in the same compartment, resulting in the formation of increasing amounts of peroxynitrite (ONOO–). As a consequence, the bioavailability of NO is decreased. This reduced level of NO and excessive accumulation of ONOO– causes a reduction in cerebral blood flow (CBF) and thus hypoxia/hypoperfusion. This “ADMA-induced uncoupling” of eNOS is maintained by sustained and prolonged production of ONOO– in a vicious cycle (Figure 1). This cycle leads to secondary injury to the neurovascular unit and, thus, cerebrovascular dysfunction and functional deficits (Choi et al., 2020). Because the role of high levels of ADMA has been established in cerebrovascular pathologies, including Alzheimer’s disease and stroke (Choi et al., 2020; Grosse et al., 2020; Selley, 2003), the discussion in this perspective is limited to ADMA/SDMA-induced aberrant activity of eNOS and its consequences on cellular functions and functional deficits.