In Parkinson's disease, together with the classic loss of dopamine neurons of the substantia nigra pars compacta, neuropathological studies and biochemical findings documented the occurrence of a concomitant significant cell death in the locus coeruleus. This review analyzes the latest data obtained from experimental parkinsonism indicating that, the loss of norepinephrine in Parkinson's disease might worsen the dopamine nigrostriatal damage. Within this latter context, basic research provided a new provocative hypothesis on the significance of locus coeruleus in conditioning the natural history of Parkinson's disease. In particular, the loss of a trophic influence of these neurons might be crucial in increasing the sensitivity of nigrostriatal dopamine axons to various neurotoxic insults. In line with this, recently, it has been shown that locus coeruleus activity plays a pivotal role in the expression of various immediate early genes and in inducing the phosphorilation of cyclic adenosine monophosphate response element-binding proteins, suggesting a role of the nucleus in sustaining a protective effect.