Following the introduction of cancer cells into the lymphatic system, metastases in 'down-stream' lymph nodes often appear in a sequential manner. This could be due to synchronous seeding of the in-line nodes with progressively diminishing numbers of tumorigenic cancer cells, or alternatively, by discrete, stepwise (metachronous) seeding of 'down-stream' nodes by 'up-stream' nodal metastases acting as 'generalizing' sites. Metachronous seeding to local lymph nodes is potentially curable by elective lymph node dissection; synchronous seeding is not. Synchronous versus metachronous seeding of lymph node metastases was investigated using the MT-100-TC mammary carcinoma injected into the hind foot-webs of rats. When the primary tumor was removed by amputation one week after injection, 1/15 animals survived; in contrast, removal of the draining popliteal lymph node in addition to the primary lesion, resulted in 8/19 long-term survivors. At this time, occult metastases detectable by bioassay but not by conventional histology, were present in all draining popliteal nodes and in 60 percent of lungs. The fact that some amputees were cured when the popliteal node was removed, indicated the metachronous nature of nodal metastases in this system. Further, recurrence of nodal and lung metastases in those amputees in which the popliteal node was left intact, identified the popliteal node as a 'generalizing' site. By the time popliteal node involvement was evident by conventional histology, micrometastases were present in 'down-stream' nodes, and accordingly, removal of the popliteal node and the primary lesion at this time was not curative.