This chapter describes efforts to develop a T cell immunotherapeutic approach for the treatment of cancer, based on the ability to identify, isolate, and expand lymphoid cells with antitumor reactivity from mice with progressive tumors. The principles and methodology established in these animal tumor models are helpful in constructing strategies to identify features essential for the success of similar approaches in man. In adoptive immunotherapy, it is clear that the availability of sensitized antitumor T lymphocytes is the most essential component for mediating tumor regression. However, in normal, unirradiated animals, adoptive immunotherapy was effective in mediating the regression of pulmonary metastases, while, within the same host, the dermal tumors were refractory to the action of transferred cells. The In Vitro Sensitization (IVS) procedure we described allows the proliferation as well as the increase of in vivo function of previously sensitized lymphocytes. Taken together, the results indicate that the IVS culture system induced cellular differentiation of therapeutic T lymphocytes.