Numerous studies have indicated that four interacting factors, including oxidative stress, mitochondrial alterations, calcium dyshomeostasis and inflammation, play crucial pathological roles in multiple major neurological diseases, including stroke, Alzheimer's disease (AD) and Parkinson's disease (PD). Increasing evidence has also indicated that NAD(+) plays important roles in not only mitochondrial functions and energy metabolism, but also calcium homeostasis and inflammation. The key NAD(+)-consuming enzyme--poly(ADP-ribose) polymerase-1 (PARP-1) and sirtuins--have also been shown to play important roles in cell death and aging, which are two key factors in the pathology of multiple major age-dependent neurological diseases: PARP-1 plays critical roles in both inflammation and oxidative stress-induced cell death; and sirtuins also mediate the process of aging, cell death and inflammation. Thus, it is conceivable that increasing evidence has suggested that NAD(+) metabolism and NAD(+)-dependent enzymes are promising targets for treating a number of neurological illnesses. For examples, the key NAD(+)-dependent enzymes SIRT1 and SIRT2 have been indicated to strongly affect the pathological changes of PD and AD; PARP-1 inhibition can profoundly reduce the brain injury in the animal models of multiple neurological diseases; and administration of either NAD(+) or nicotinamide can also decrease ischemic brain damage. Future studies are necessary to further investigate the roles of NAD+ metabolism and NAD⁺-dependent enzymes in neurological diseases, which may expose novel targets for treating the debilitating illnesses.