Among the potential cancer immunotherapies, vaccination against antigens expressed by endothelial cells lining the tumor vasculature represents one of the most attractive options because this approach may prevent the growth of any solid tumor. Therefore, endothelial cells can be used as a source of antigens for developing a so-called "universal" cancer vaccine. Unfortunately, efficient endothelial cell-based cancer vaccines have not yet been developed because previous approaches utilized direct endothelial cell immunizations which is not effective and can result in the elicitation of autoimmune responses associated with systemic autoimmune vasculitis. Recently, the heterogeneity of the endothelial cell surface was defined using an in vitro system as a means of developing antiangiogenic cancer vaccines. This analysis demonstrated that tumors induced specific changes to the microvascular of human endothelial cell (HMEC) surface thereby providing a basis for the design of endothelial cell-based vaccines that directly target the tumor endothelium. (1) This commentary further describes HMEC heterogeneity from the perspective of designing an endothelial cell-based universal (for the treatment of all solid tumors) cancer vaccine with high immunogenicity that does not pose the risk of eliciting autoimmunity.