Malignant tumors of ectodermal or endodermal origin may metastasize to the sentinel lymph node, the first lymph node encountered by tumor cells that enter lymphatics in the organ of origin. This pathway is enabled by the anatomy of the disease and the causes of metastasis are the result of complex interactions that include mechanical forces within the tumor and host tissues, and molecular factors initiated by tumor cell proliferation, elaboration of cytokines and changes in the tumor microenvironment. Mechanical stresses may influence complex biochemical, genetic and other molecular events and enhance the likelihood of metastasis. This paper summarizes our understanding of interacting molecular, anatomical and mechanical processes which facilitate metastasis to SLNs. Our understanding of these interacting events is based on a combination of clinical and basic science research, in vitro and in vivo, including studies in lymphatic embryology, anatomy, micro-anatomy, pathology, physiology, molecular biology and mechanobiology. The presence of metastatic tumor in the SLN is now more accurately identifiable and, based upon prospective clinical trials, paradigm-changing SLN biopsy has become the standard of clinical practice in breast cancer and melanoma.