<p>The concept of structural immunity, as defined in this Perspective, posits that the first line of immune defence against foreign agents and tissue damage involves the preventative, physical reinforcement of tissue barriers and that this fundamental task can be directly or indirectly regulated by immune cells. Indeed, several types of leukocytes can help build protective barriers when required, potentially either by depositing matrix components themselves in certain circumstances or, more generally, by interactions with canonical structural cells and the existing extracellular matrix. This concept of structural functions of immune cells challenges the rigidity with which mammalian tissue organization and immune defence have been traditionally compartmentalized. Although there is strong momentum in the evidence for structural immunity that has been acquired so far, the field lacks a comprehensive overview of these data as well as a critical evaluation of this concept. Here, we place independent findings from several groups into a working model of immune cells as the architects of tissue barriers, to present a framework on which new concepts and findings in this area can develop.</p>