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Major histocompatibility complexes (MHC) have been used for more than two decades in clinical and pre-clinical approaches of tumor immunotherapy. They have been proven efficient for detecting anti-tumor-specific T cells when utilized as soluble multimers, immobilized on cells or artificial structures such as artificial antigen-presenting cells (aAPC) and have been shown to generate effective anti-tumor responses. In this review we summarize the use of soluble MHC class I complexes in tumor vaccination studies, highlighting the different strategies and their contradicting results. In summary, we believe that soluble MHC class I molecules represent an exciting tool with great potential to impact the understanding and development of immunotherapeutic approaches on many levels from monitoring to treatment.