Extracellular matrix (ECM) in the brain is composed of molecules synthesized and secreted by neurons and glial cells in a cell-type-specific and activity-dependent manner. During development, ECM plays crucial roles in proliferation, migration and differentiation of neural cells. In the mature brain, ECM undergoes a slow turnover and supports multiple physiological processes, while restraining structural plasticity. In the first part of this review, we discuss the contribution of ECM molecules to different forms of plasticity, including developmental plasticity in the cortex, long-term potentiation and depression in the hippocampus, homeostatic scaling of synaptic transmission and metaplasticity. In the second part, we focus on pathological changes associated with epileptogenic mutations in ECM-related molecules or caused by seizure-induced remodeling of ECM. The available data suggest that ECM components regulating physiological plasticity are also engaged in different aspects of epileptogenesis, such as dysregulation of excitatory and inhibitory neurotransmission, sprouting of mossy fibers, granule cell dispersion and gliosis. At the end, we discuss combinatorial approaches that might be used to counteract seizure-induced dysregulation of both ECM molecules and extracellular proteases. By restraining ECM modification and preserving the status quo in the brain, these treatments might prove to be valid therapeutic interventions to antagonize the progression of epileptogenesis.