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The application of immunologic methods to the treatment of neoplasia has been a goal of research in tumor immunology. Unfortunately, no clearly defined success for such therapy has been achieved. However, the most recent advances in tumor biology have provided for a more valid conceptual framework upon which to plan further research in this area. The more general awareness of tumor progression and heterogeneity, particularly in the context of tumor metastasis, while imposing a sense of gloom regarding all therapeutic modalities, shifted immunologic thinking toward the development of nonspecific modalities. We herein propose that this ‘shift’ may be premature and that immunotherapy using cytolygic T cells could still be feasible. Our views are based on newer approaches for selecting immunogenic variants of malignant tumors and a better understanding of the relationship of the immune response to metastases.