Nardilysin is a metalloprotease that cleaves peptides, such as dynorphin-A, α-neoendorphin, and glucagon, at the N-terminus of arginine and lysine residues in dibasic moieties. It has various functionally important molecular interaction partners (heparin-binding epidermal growth factor-like growth factor, tumour necrosis factor-α-converting enzyme, neuregulin 1, beta-secretase 1, malate dehydrogenase, P42(IP4)/centaurin-α1, the histone H3 dimethyl Lys4, and others) and is involved in a plethora of normal brain functions. Less is known about possible implications of nardilysin for brain diseases. This review, which includes some of our own recent findings, attempts to summarize the current knowledge on possible roles of nardilysin in Alzheimer disease, Down syndrome, schizophrenia, mood disorders, alcohol abuse, heroin addiction, and cancer. We herein show that nardilysin is a Janus-faced enzyme with regard to brain pathology, being probably neuropathogenic in some diseases, but neuroprotective in others.