Secondary lymphoid organs (SLO), including the spleen and lymph nodes (LN) are a meeting place for immune cells to initiate adaptive immune responses. Lymphocytes constantly circulate between SLO through the blood and lymph in search of their cognate antigen and are activated within the organized microarchitecture of SLO. Lymphoid stromal cells (LSC) of mesenchymal and endothelial origin construct and support the microarchitecture of SLO by defining distinct compartments and providing signals that can either promote or inhibit immune responses. Here, we discuss recent studies indicating that LSC, including fibroblastic reticular cells (FRC), contribute substantially to immune responses and may tune responses to secondary challenge.