An ideal vaccination strategy against tumors relies on specific antigens that are required for tumor maintenance. For lymphoma, vaccination with subject-specific immunoglobulin idiotypes has had the most promising results^,. Here we show that DNA vaccination with plasmids encoding portions of the cytoplasmic domain of anaplastic lymphoma kinase (ALK), which has been translocated in different fusion proteins necessary for the growth of anaplastic large cell lymphoma (ALCL), protects mice from local and systemic lymphoma growth. The protection is potent and long lasting and elicits ALK-specific interferon-γ responses and CD8⁺ T cell–mediated cytotoxicity. A combination of chemotherapy and vaccination significantly enhanced the survival of mice challenged with ALK⁺ lymphomas. These findings indicate that ALK represents an ideal tumor antigen for vaccination-based therapies of ALCL and possibly other ALK⁺ human tumors^,,,.