Abstract: Sentinel lymph node biopsy is widely used in melanoma, breast cancer, and other malignancies. Main tracers used are radiotracers, vital blue dyes, and near-infrared fluorescent dyes; however, all have a problem with nonspecific uptake in secondary lymph nodes. The new specific-targeted sentinel node agents, which target points such as CD20 (presenting on the membrane of B lymphocytes) and CD206 (expressing on macrophages and dendritic cells), can be labeled with nuclide, fluorescence, or both. Compared with commonly used agents, these new tracers exhibit rapid clearance from the injection site, rapid uptake, high retention within the sentinel node, and low uptake by distal lymph nodes, thus satisfying the properties of an ideal lymph node imaging agent. A specific-targeted fluorescent radiopharmaceutical approach aims to apply pre-surgical nuclear imaging and intra-operative fluorescence imaging for the sentinel node localization of cancers, such as prostate and colon cancer. This article reviews and summarizes the research progress on these new specific-targeted agents.