Parkinson’s disease (PD) is a neurologic disorder resulting from the loss of dopaminergic neurons in the brain. Two lines of evidence suggest that the protein α-synuclein plays a role in the pathogenesis of PD: Fibrillar α-synuclein is a major component of Lewy bodies in diseased neurons, and two mutations in α-synuclein are linked to early-onset disease. Accordingly, the fibrillization of α-synuclein is proposed to contribute to neurodegeneration in PD. In this report, we provide evidence that oligomeric intermediates of the α-synuclein fibrillization pathway, termed protofibrils, might be neurotoxic. Analyses of protofibrillar α-synuclein by atomic force microscopy and electron microscopy indicate that the oligomers consist of spheres, chains, and rings. α-Synuclein protofibrils permeabilize synthetic vesicles and form pore-like assemblies on the surface of brain-derived vesicles. Dopamine reacts with α-synuclein to form a covalent adduct that slows the conversion of protofibrils to fibrils. This finding suggests that cytosolic dopamine in dopaminergic neurons promotes the accumulation of toxic α-synuclein protofibrils, which might explain why these neurons are most vulnerable to degeneration in PD. Finally, we note that aggregation of α-synuclein likely occurs via different mechanisms in the cell versus the test tube. For example, the binding of α-synuclein to cellular membranes might influence its self-assembly. To address this point, we have developed a yeast model that might enable the selection of random α-synuclein mutants with different membrane-binding affinities. These variants might be useful to test whether membrane binding by α-synuclein is necessary for neurodegeneration in transgenic animal models of PD.