It has been assumed that T cells induced at one tumor site can travel to distant tumor sites to mediate regression and that the immunity induced and its immune regulation are both determined by the biology of the tumor’s internal microenvironment, not its anatomic location.  The role of different tissue locations in immune regulation and protections, and the crosstalk between different tissue sites, is not well explored.  Here, we examined the immune regulation and T cell protective mechanisms when the same tumor, the BALB/c colon carcinoma CT26, is in the lungs versus subcutaneous sites in the same mouse.  We find differences in both immune regulation and immunity arising when that regulation is removed.  Lack of NKT cells in CD1d^-/- mice leads to tumor rejection in the lungs, but not in the skin, whereas depletion of CD25⁺ Treg cells protects in the skin but not in the lungs.  Furthermore, the T cells induced after Treg depletion in the presence of subcutaneous tumor can also prevent tumor growth in the lungs of that mouse, but the converse is not true:  the T cells that protect the lungs when NKT cells are absent do not protect against tumors in the skin of the same mouse. Also, splenic CD4⁺ and/or CD8⁺ cells from Treg-depleted subcutaneous tumor-bearing mice protect RAG^-/- mice from tumors at both sites, whereas T cells from CD1d^-/- mice rejecting lung tumors protect RAG^-/- recipients from lung but not subcutaneous tumors.  Thus, there is asymmetry in the memory T-cell cross-talk between these sites.  This work demonstrates the surprising importance of tissue location, even when the tumor and mouse are identical, in determining what regulatory mechanisms are dominant and what spectrum of T cell immunity is induced.  This has important implications for immunotherapy of primary and metastatic tumors.