The proteome is the protein compliment of the genome and is the result of genetic expression, ribosomal synthesis and proteolytic degradation. Proteins participate in most major cell processes and their function is highly regulated by post-translational modifications such as phosphorylation and glycosylation. As a result, neurotoxicant-induced changes in protein levels, function or regulation could have a negative impact on neuronal viability. At the molecular level, direct oxidative or covalent modifications of individual proteins by various chemicals or drugs is likely to lead to perturbation of tertiary structure and a loss of function. The proteome and the functional determinants of its individual protein components are, therefore, likely targets of neurotoxicant action and resulting characteristic disruptions could be critically involved in corresponding mechanisms of neurotoxicity. Clearly, investigating changes in the proteome can provide important clues for deciphering mechanisms of toxicant action and, therefore, proteomics, the study of the proteome, is currently, and will likely remain, a significant experimental approach for mechanistic research in neurotoxicology. The purpose of this review is to discuss proteomics as a tool for neurotoxicological investigations. A variety of classic proteomic techniques (e.g. liquid chromatography (LC)/tandem mass spectroscopy, two-dimensional gel image analysis) as well as more recently developed approaches (e.g. two-hybrid systems, antibody arrays, protein chips, isotope-coded affinity tags, ICAT) are available to determine protein levels, identify components of multiprotein complexes and to detect post-translational changes. Proteomics, therefore, offers a comprehensive overview of cell proteins, and in the case of neurotoxicant exposure, can provide quantitative data regarding changes in corresponding expression levels and/or post-translational modifications that might be associated with neuron injury.