Because T lymphocytes have the capacity to recognize tumor cells, significant efforts are being devoted towards the development of T cell-based immunotherapy for cancer. Most of this work has centered in the induction of anti-tumor CD8 T cells, which exhibit cytolytic activity towards tumor cells expressing tumor-specific or tumor associated antigens. Unfortunately to this day, T cell-based immunotherapy for cancer remains suboptimal. One of the possible explanations is that these immunotherapies have ignored the role that CD4 T helper lymphocytes play in the generation and persistence of CD8 T cell responses. Thus, we believe that in order to obtain clinical benefits T cell-based immunotherapy must stimulate both CD8 and CD4 tumor-reactive T cell responses. During the past seven years our group has focused on the identification of CD4 T cell epitopes from tumor-associated and tumor-specific antigens that could be used to complement the already identified CD8 T cell epitopes to produce effective vaccination strategies against numerous tumor types. We will describe here the strategy we used that resulted in the identification and characterization of numerous CD4 T cell epitopes that are applicable to developing therapies against hematological malignancies and solid tumors.