Lymph node (LN) fibroblastic reticular cells (FRCs) are key regulators of mammalian adaptive immune responses. Together with their deposited extracellular matrix (ECM), FRCs form a reticular network that provides mechanical strength to LNs. Furthermore, the ECM regulates various cell functions including proliferation and differentiation. The ECM is dynamically remodeled in activated LNs, thereby affecting immune cell survival and function. Although both the LN ECM and FRCs can affect immune reactivity, a link between altered LN ECM during an immune response and ECM-producing FRCs is lacking. We explore recent work on the complex interplay between FRCs, ECM, and immune cells in health and disease, and provide guidance for future research to understand the complex regulation of the adaptive immune system within LNs.