Mycoplasmas are responsible for many human and animal respiratory diseases and have a tremendous economic and health impact worldwide. Currently, there is no vaccine against any animal or human mycoplasma species. Despite the vast amount of research, the mechanisms that control hosts' resistance and susceptibility to mycoplasma infection remains unclear. Immune responses, particularly T lymphocyte responses, are believed to be critical players in the pathogenesis of mycoplasma disease. In this review, we will highlight the potential roles of T lymphocytes as influential mediators in animal and human mycoplasma pathogenesis and resistance infection.