An essential component of the brain extracellular space is the extracellular matrix contributing to the spatial assembly of cells by binding cell-surface adhesion molecules, supporting cell migration, differentiation, and tissue development. The most interesting and complex functions of the central nervous system are the abilities to encode new information (learning) and to store this information (memory). The creation of perineuronal nets, consisting mostly of chondroitin sulfate proteoglycans, stabilizes the synapses and memory trails and forms protective shields against neurodegenerative processes but terminates plasticity and the potential for recovery of the tissue. Age-related changes in the extracellular matrix composition and the extracellular space volume and permissivity are major determinants of the onset and development of the most common neurodegenerative disorder, Alzheimer's disease. In this regard, heparan sulfate proteoglycans, involved in amyloid clearance from the brain, play an important role in Alzheimer's disease and other types of neurodegeneration. Additional key players in the modification of the extracellular matrix are matrix metalloproteinases. Recent studies show that the extracellular matrix and matrix metalloproteinases are important regulators of plasticity, learning, and memory and might be involved in different neurological disorders like epilepsy, schizophrenia, addiction, and dementia. The identification of molecules and mechanisms that modulate these processes is crucial for the understanding of brain function and dysfunction and for the design of new therapeutic approaches targeting the molecular mechanism underlying these neurological disorders.