Heat shock proteins have been the focus of many experimental studies during the last few years in order to understand their biology and their imunologic features. We conducted pre-clinical experiments showing that gp96 purified from human melanoma lines can represent melanoma antigens and stimulate T cells known to recognize such antigens. Clinical studies of vaccination were then initiated by our group by using heat-shock protein gp96 purified from autologous tumor tissues in patients with melanoma and colorectal carcinoma. The results of these trials in metastatic melanoma patients with measurable disease showed that a melanoma-specific T cell response can be generated or increased in approximately 50% of vaccinated patients. Moreover, signs of clinical responses were obtained consisting of two complete responses and three long-lasting stabilizations. Similar results were obtained in patients with liver metastases of colorectal cancer made disease-free by surgery. In both studies a clear association was found between T cell immune response induced by the vaccine and clinical response both in the trial of melanoma (tumor response) and in that of colorectal cancer patients (disease-free and overall survival at 5 years).