It is generally accepted that both self- and pathogen-specific T lymphocytes have the potential to mediate immunopathogenesis and contribute to a variety of human ailments. Despite this unfortunate tendency to induce tissue injury, these cells are guided by interactions with peptide-loaded major histocompatibility complexes (MHC) and adhere appropriately to a vital evolutionary constraint imposed by the host: specificity. More recently, a series of studies have demonstrated that bystander T cells of an irrelevant specificity can bypass peptide/MHC restriction and become active participants in immunopathology. This review critically evaluates the role of bystander T cells in immunopathogenesis and pathogen clearance in the periphery as well as the central nervous system and attempts to establish the likelihood of their participation in human disease.