The migration of naïve T cells to secondary lymphoid organs and their subsequent encounter with dendritic cells (DCs) ensures the efficient priming of adaptive T cell-mediated immune responses. The expression of particular sets of adhesion molecules and chemokine receptors allows effector T cells and natural killer (NK) cells to migrate to inflamed non-lymphoid tissues. Thus, the segregation of immune functions by specialized cell subsets relies in part on their migratory competence. Recent studies have shown, however, that NK cells and effector T cells can migrate to activated lymph nodes and impact on the magnitude and quality of the primary T cell response. This is in part due to inflammation-related events that modify the adhesive properties of the high endothelial venules (HEVs). In this review we highlight recent findings that challenge the current idea of the lymph node as an exclusive niche for naive T cells and underline the unique role that NK cells and effector T cells have in models of acute and chronic inflammation when recruited to peripheral lymph nodes.