How the brain performs higher cognitive functions such as learning and memory is traditionally studied by investigating how neurons work. However, over the past two decades, evidence has accumulated which suggests that components of the extracellular matrix contribute to the storing of information through learning processes. Thus, matrix regulation – either changes in the protein composition of the perineural network surrounding neurons or cleavage of this network by specific metalloproteases – could be relevant to the many psychiatric disorders that are shaped by previous experiences, i.e. by learning and plasticity. This includes disorders which are a direct consequence of past experiences and ones where previous experiences constitute a risk factor. Psychotherapy is one of the first-line treatments for most psychiatric conditions, and involves learning and plasticity. Here, we review selected publications pertaining to experience dependence in psychiatric conditions and summarise evidence of roles for the extracellular matrix in learning and memory. We then suggest how control of the extracellular matrix could be leveraged for innovative treatments and, more generally, discuss possible aetiological effects of extracellular matrix alterations in psychiatric disorders.