Given the complexity of brain and nerve tissues, systematic approaches are essential to understand normal physiological conditions and functional alterations in neurological diseases. Mass spectrometry-based proteomics is increasingly used in neurosciences to determine both basic and clinical differential protein expression, protein-protein interactions, and post-translational modifications. Proteomics approaches are especially useful to understand the mechanisms of nerve regeneration and degeneration because changes in axons following injury or in disease states often occur without the contribution of transcriptional events in the cell body. Indeed, the current understanding of axonal function in health and disease emphasizes the role of proteolysis, local axonal protein synthesis, and a broad range of post-translational modifications. Deciphering how axons regenerate and degenerate has thus become a postgenomics problem, which depends in part on proteomics approaches. This review focuses on recent proteomics approaches designed to uncover the mechanisms and molecules involved in neuronal regeneration and degeneration. It emerges that the principal degenerative mechanisms converge to oxidative stress, dysfunctions of axonal transport, mitochondria, chaperones, and the ubiquitin-proteasome systems. The mechanisms regulating nerve regeneration also impinge on axonal transport, cytoskeleton, and chaperones in addition to changes in signaling pathways. We also discuss the major challenges to proteomics work in the nervous system given the complex organization of the brain and nerve tissue at the anatomical, cellular, and subcellular levels.