AbstractThe mechanisms by which malignant tumors leave the primary tumor site, invade lymphatics, and metastasize to regional lymph nodes (RLNs) are complex and interrelated. Although the phenomenon of lymph node metastasis has been recognized for over 200 years, the exact mechanisms have only recently been the subject of intense interest and sophisticated experimentation. Sentinel lymph node biopsy has rapidly entered the clinical mainstream for melanoma and breast carcinoma, and this technique has provided confirmation of the orderly anatomic progression of tumor cells from primary site to the RLNs through lymphatic capillaries and trunks. Exciting studies involving the pathophysiology of interstitial fluid pressure in tumors and the peritumoral extracellular matrix have focused on lymphatic flow and tumor microenvironment and microcirculation. Molecular techniques have led to the definition of unique markers found on lymphatic endothelial cells. These markers have enabled scientists to identify peritumoral and intratumoral lymphatics and to visualize the ingrowth of tumor cells into the lumena of lymphatic capillaries. Tumor‐secreted cytokines, such as vascular endothelial growth factors (VEGF)‐C and ‐D, bind to VEGF receptors on lymphatic endothelial cells and induce proliferation and growth of new lymphatic capillaries; this process is similar to the well‐known mechanism of angiogenesis, which results from the proliferation of new blood vessel capillaries. Lymphangiogenesis is associated with an increased incidence of RLN metastasis, and it is possible that this step is essential to the metastatic process. Directional movement toward lymphatics and lymph nodes appears to follow a chemokine gradient, and it is likely that some tumor cells that express certain types of chemokine receptors are more likely to metastasize to the RLNs. In contrast, tumor cells that do not express specific receptors that are responsive to lymphatic chemokines may not metastasize. New knowledge regarding the molecules involved in these processes should enable improvements in prognostic and possibly therapeutic approaches to the management of malignant tumors. Cancer 2003;98:413–23. © 2003 American Cancer Society.DOI 10.1002/cncr.11464