Bladder cancer ranks as the ninth most frequently-diagnosed cancer worldwide, with the highest incidence rates observed in men in Southern and Western Europe, North America, as well as in certaincountries in Northern Africa or Western Asia. Incidence rates are consistently lower in women than men, although sex differences varied greatly between countries. Even though 70 to 80% of patients are diagnosed with superficial disease, bladder cancer has a high overall rate of recurrence at approximately 65%. Since the pioneering work of Morales et al. in 1976, intravesical BCG has been the standard-of-care immunotherapy for superficial bladder cancer. BCG immunotherapy results in 70–75% and 50–60% complete response rates for carcinoma-in situ and small residual tumors, respectively. Unfortunately, a significant percentage of patients will fail initial BCG therapy and approximately 30–50% of BCG responders will develop recurrent tumors within 5 years [4, 5]. Therefore, despite the effectiveness of BCG, additional therapies are needed to limit recurrence and improve survival for both BCG responders and non-responders. Evaluation of the genomic data of bladder cancer has shown that about half of patients as having highly mutated tumors [6]. While other tumors have a lower mutational burden, these can be characterized by dozens of gene amplifications. Both mutated proteins and overexpressed proteins can be exploited as tumor antigens and potential vaccine candidates. Currently, the most common tumor antigens exploited in cancer immunotherapy are up-regulated self-proteins, such as HER2. While mutated epitopes are recognized as foreign “net-antigens” by the immune system eliciting Type I response, epitopes derived from non-mutated self antigens are more likely to trigger Th2 polarizing cytokines such as IL-10 and IL-6 that inhibit CTL proliferation and function. Recently attempts have been made to identify Th1 selective epitopes from non-mutated self-antigens that could elicit a “neo-antigen” like response. The Th1 selective epitopes, when used in a vaccine, can elicit unopposed Type I immunity and are effective in preventing cancer growth in pre-clinical models. If Th2 inducing epitopes from the same protein are included in a vaccine, Th2 cells elicited by immunization will abrogate the anti-tumor effect of Th1. Therefore, the vaccines composed only of Th1 inducing epitopes may allow unrestricted expansion of both Th1 and CTL. Th1 selective non-mutated antigen vaccines may be effective in preventing disease recurrence and progression. If the antigens are expressed early in oncogenesis, vaccines could have utility in prevention. Novel and more promising target antigens for preventive cancer vaccines may be identified from careful analyses of molecular alterations such as overexpressed genes in premalignant and/or malignant tissues discovered through the TCGA and other cancer genomics projects. Some of the genes overexpressed in premalignant and malignant lesions, but not in normal tissues, could be immunogenic and capable of eliciting protective antitumor immune responses. High priority candidate genes can be selected from the list of overexpressed genes by employing a systematic approach, for example, based on differential expression patterns between premalignant or malignant lesions vs. normal tissues, functional roles in physiologic or oncogenic signaling pathways, and immunogenicity prediction and in vitro screening processes. Once candidate target proteins are selected, peptide based vaccines may be designed, and can be preclinically tested for in vivo immunogenicity and tumor preventive efficacy in relevant models. These kind of rational design strategies may help expedite the discovery and development of an efficacious cancer vaccine for prevention of various cancers including cancer of the bladder.