The ionic compound 1-methyl-4-phenylpyridinium ion (MPP⁺) is the main metabolite of the parkinsonizing drug MPTP and it seems to be the neurotoxic agent responsible for dopaminergic neurodegeneration. Since its discovery much has been learnt about its molecular mechanisms of action. MPP⁺ is taken up by dopaminergic terminals using the dopamine-reuptake mechanisms. Inside the cell, the MPP⁺ can be stored in dopaminergic vesicles or indroduced into the mitochondria. The distribution between these two compartments seems to be crucial to an explanation of the toxic effects of MPP⁺. Inside the mitochondria MPP⁺ inhibits several enzyme activities, with a prominent role in the inhibition of monoamine oxidase and mitochondrial complex I NADH-dehydrogenase. The latter effect leads to a hypoxic-like condition, with energy failure and free oxygen radicals production. Since rats are particularly resistant to MPTP neurotoxicity and MPP⁺ does not cross the blood-brain-barrier, MPP⁺ has often been injected directly into the rat brain in order to reproduce the effects of MPTP. Intranigral, intrastriatal or intracerebroventicular administrations, by injection or perfusion, are widely used. Although MPP⁺ administered in this way causes a marked depletion of dopamine in the rat brain, its effects are different from the selective effects described for MPTP in primates and mice. Why the effects of MPTP in some animals are difficult to reproduce in vivo by MPP⁺ in other animals is still an open question. Moreover, the mechanisms of cell death mediated by MPP⁺ are not yet completely understood. The interest for such question is to answer whether there could be any endogenous compound whose accumulation in the brain could mimic the MPP⁺ effects, leading to the nigrostriatal degeneration found in Parkinson’s disease. Recent advances have provided new perspectives about the role not only of oxygen radicals but also of NO production in MPP⁺ toxicity. It seems that a cascade of event may be triggered by MPP⁺ at different steps in a concentration-dependent manner. We present a review of the results obtained in rats by MPP⁺ in vivo and the present status of knowledge of its molecular mechanisms of action, in an attempt to advance some explanation about the differences between MPTP and MPP⁺-treatments