Immunotherapy that aims to boost the body's immune responses against pathogens or diseased cells has achieved significant progress for treating different diseases over the past several decades, especially with the success of checkpoint blockades, chimeric antigen receptor T therapy, and cancer vaccines in clinical cancer treatment. Effective immunotherapy necessitates the generation of potent and persistent humoral and T-cell responses, which lies in the ability of modulating and guiding antigen-presenting cells to prime antigen-specific T and B cells in the lymphoid tissues, notably in the lymph nodes proximal to the disease site. To this end, various types of strategies have been developed to facilitate the delivery of immunomodulatory agents to immune cells (e.g. dendritic cells and T cells) in the lymph nodes. Among them, intranodal injection enables the direct exposure of immunomodulators to immune cells in lymph nodes, but is limited by the technical challenge and intrinsic invasiveness. To address, multiple passive and active lymph node-targeting technologies have been developed. In this review, we will provide an overview of different lymph node-targeting technologies developed to date, as well as the mechanism and merits of each approach.