Antigen delivery to antigen-presenting cells (APCs) is a key issue in developing effective cancer vaccines. Controlling the tissue distribution of antigens, which are administered in a peptide/protein or DNA form, can increase antigen-specific immune responses, including the induction of cytotoxic T lymphocytes. Heat-shock protein 70 (Hsp70), a member of a highly conserved family of molecular chaperones, forms complexes with a variety of tumor-related antigens via its polypeptide binding domain. Because Hsp70 is taken up by APCs through the recognition by Hsp receptors, such as CD91 and LOX-1, its application to antigen delivery systems has been examined both in experimental and clinical settings. A tissue distribution study revealed that Hsp70 is mainly taken up by the liver, especially by hepatocytes, after intravenous injection in mice. A significant amount of Hsp70 was also delivered to regional lymph nodes when it was injected subcutaneously, supporting the hypothesis that Hsp70 is a natural targeting system to APCs. Model antigens were complexed with or conjugated to Hsp70, by which greater antigen-specific immune responses were achieved. Cytoplasmic delivery of Hsp70-antigen further increased the efficacy of the Hsp70-based vaccines. These findings indicate that effective cancer therapy can be achieved by developing Hsp70-based anticancer vaccines when their tissue and intracellular distribution is properly controlled.