Regulatory T lymphocytes play a central role in maintaining an immunological balance between responsiveness to foreign antigens and suppression of responsiveness to self-antigens. We recently discovered that infection of mice with Friend retrovirus skewed the balance toward suppression by causing an expansion of immunosuppressive regulatory cells. Immunosuppression was transferable to naive mice by adoptive transfer of CD4+ T cells. Our current studies examine the in vivo role of CD4+ regulatory T lymphocytes in controlling normal immune responses and investigate ways to prevent or reverse immunosuppression by these cells. Regulatory cells have now been implicated as factors in the establishment and/or maintenance of persistence in human infections with parasites, Bordetella pertussis, hepatitis C virus, and HIV. Thus findings from the Friend virus mouse model may provide insights into new therapies or preventive strategies against persistent pathogens.