Neuromelanin (NM) accumulates as a function of age in normal human substantia nigra (SN) but is relatively depleted in the SN of patients with Parkinson disease (PD). Several studies have been performed to further our understanding of the role of NM in neuronal aging and neurodegenerative mechanisms of PD. To this purpose, NM from human SN was isolated and its structure and molecular interactions were investigated. Cysteinyl-dopamine was shown to be one precursor of NM synthesis. A striking affinity of NM for specific metals, lipids, drugs and pesticides was found in vitro, and in animal and human brain postmortem studies. Because of these affinities, NM seems to play a protective role in the human brain by blocking toxic molecules. On the other hand, experiments in cell culture indicate that NM can activate microglia, eliciting the release of cytotoxic factors that can induce neurodegeneration.