T lymphocytes play a major role in the recognition and subsequent elimination of tumors and intracellular pathogens. Induction of epitope-specific T cell responses can help in the clearance of diseases for which no conventional vaccines exist. However, the lack of simple methods to identify relevant T cell epitopes, the high mutation rate of many pathogens, and HLA polymorphism have made the development of efficient T cell epitope-based, or "epitope-driven" vaccines difficult to achieve. Our research over the past several years has applied bioinformatics tools in conjunction with T cell assays to identify naturally processed putative T cell epitopes from several pathogens. This strategy will accelerate the development of new generation T cell epitope-based vaccines against various pathogens including viruses such as HIV and WNV, bacteria such as M.tb., and parasites such as plasmodium. This chapter will review the use of a bioinformatics-based approach to identify putative T cell epitopes. It will summarize the current state of knowledge regarding T cell-epitope-based vaccines and discuss several ways to improve their efficacy.