The extracellular matrix (ECM) of the brain is a complex meshwork of molecules that surrounds and supports neuronal and non-neuronal brain cells. The major components of the brain ECM include glycosaminoglycans (GAGs), proteoglycans (PGs), hyaluronan and matrix-degrading enzymes. The most important components are chondroitin sulfate PGs lecticans which form aggregates with other matrix components and contribute to the formation of perineuronal nets (PNNs) that are unique to the central nervous system. PNNs are matrix molecule assemblies surrounding neuronal somata, dendrites and axon initial segments in a lattice-like appearance. PNNs play a pivotal role in maintaining the integrity of the matrix and preserving existing synapses which is crucial for long-term memory consolidation. ECM is part of the “tetrapartite” synapse which also involves pre-synaptic and post-synaptic neurons, as well as astrocytes, and it is the key to maintaining physiological microenvironment at the synaptic cleft and propagation of nerve impulses. The brain ECM plays a central role in various physiological and pathological processes, such as cell proliferation, cell migration, apoptosis, synaptic plasticity, myelination, neuroinflammation, and neurodegeneration. Defects in ECM components or their dysregulation have been implicated in various neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Research on the brain ECM is a rapidly evolving area that holds great promise for the development of novel therapeutic strategies for the disorders of the central nervous system.