Parkinson's disease is predominantly a dopamine deficiency syndrome, which is produced in the brain by the loss of cells located in a small area in the ventral midbrain called the substantia nigra. Complete unilateral dopamine lesions, based on the administration of toxic substances (ie, 6-hydroxy-dopamine in rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice and primates) have been extremely useful in testing strategies of replacement. For example, the functional and biochemical impact of the transplanted ventral mesencephalic dopaminergic progenitors has been characterized to a large extent, using the complete lesion model in rats. Over the last decade, however, studies addressing the ability of neurotrophic factors to protect injured dopamine cells prompted researchers to make available partial and progressive lesion models to allow a window of opportunity to interfere the disease progression. Recent findings relating alpha-synuclein with Parkinson's disease pathology have opened new possibilities to develop alternative models based on the overexpression of this protein using recombinant adeno-associated viral vectors, which is valuable not only for helping to better understand its involvement in the disease process, but also to more closely resemble the neurodegeneration found in Parkinson's disease.