Considerable progress has been made in understanding the Fas pathway at the molecular and cellular levels, but fundamental questions about the overall biological role of the Fas pathway remain unresolved. A major question is why lymphoproliferation caused by the lpr mutation of Fas and gld mutation of FasL ligand (FasL) is dominated by CD4(-) and CD8(-) double-negative alphabeta T cells (DN T cells) that are otherwise rare components of the peripheral T cell repertoire. A second unresolved question is why inactivation of the Fas pathway prevents organ-specific autoimmunity (including as type 1 diabetes and multiple sclerosis) while causing systemic lymphoproliferation? Understanding the mechanisms of these processes could uncover important aspects of the biological role of the Fas pathway and could have significant therapeutic implications. For example, revealing the basis of how inactivation of the Fas pathway prevents organ-specific autoimmunity could lead to new immunotherapeutic strategies to promote self tolerance without causing immunosuppression, as the Fas pathway is not essential for T cell activation. Here we discuss recent and new findings from my laboratory that address these questions. On the basis of these findings, we propose a new role for the Fas pathway in sequestration of DN T cells within the gut epithelium.