The orchestration of systemic immune responses is critically dependent on coordinated lymphocyte migration and recirculation. This “homing” guides lymphocytes to the microenvironments that control their differentiation and survival, disperses the immunologic repertoire, and targets effector lymphocytes to sites of antigenic insult. Lymphocyte homing is a multistep process that requires chemotaxis and cell adhesion coupled with strategies to overcome physical barriers. At the molecular level, it is regulated by adhesion molecules and chemokines, and facilitated by intrinsic molecular programs that allow “ameboid” shape change, allowing highly effective lymphocyte traffic between different tissue compartments. In case of malignant transformation, however, the fact that lymphocytes are “licensed to move” forms a serious threat to the organism, because it permits rapid tumor dissemination irrespective of the conventional anatomic boundaries limiting early spread in most types of cancer. Thus, unlike the metastatic spread of other cancers, lymphoma dissemination generally is not a reflection of tumor progression but of conserved physiological behavior. The dissemination patterns often reflect basic rules of lymphocyte homing, explaining the strikingly tissue-specific dissemination of, for example, mucosal lymphomas, cutaneous lymphomas, and multiple myeloma. Understanding the molecular mechanisms underlying this behavior may provide novel targets for treatment of lymphoma patients.