Two decades ago, lymphatic mapping of sentinel lymph nodes (SLN) was introduced into surgical cancer management and was termed sentinel node navigated surgery. Although this technique is now routinely performed in the management of breast cancer and malignant melanoma, it is still under investigation for use in other cancers. The radioisotope technetium ((99m)Tc) and vital blue dyes are among the most widely used enhancers for SLN mapping, although near-infrared fluorescence imaging of indocyanine green is also becoming more commonly used. (99m)Tc-tilmanocept is a new synthetic radioisotope with a relatively small molecular size that was specifically developed for lymphatic mapping. Because of its small size, (99m)Tc-tilmanocept quickly migrates from its site of injection and rapidly accumulates in the SLN. The mannose moieties of (99m)Tc-tilmanosept facilitate its binding to mannose receptors (CD206) expressed in reticuloendothelial cells of the SLN. This binding prevents transit to second-echelon lymph nodes. In Phase III trials of breast cancer and malignant melanoma, and Phase II trials of other malignancies, (99m)Tc-tilmanocept had superior identification rates and sensitivity compared with blue dye. Trials comparing (99m)Tc-tilmanocept with other (99m)Tc-based agents are required before it can be routinely used in clinical settings.