Naı̈ve T cells in the draining lymph node (DLN) do not immediately respond to antigenic tissues or antigenic cancers in the periphery. Rather, the conditions under which naı̈ve T cells encounter antigen in the DLN can result in the distinct immunological states of ignorance, tolerance or immunity. Recent work suggests that these immunological states are determined by the level of antigen expressed by peripheral tissues and the maturation stage of the dendritic cell presenting the antigen. When antigens are expressed at levels that are sufficient to be cross-presented by mature dendritic cells in the DLN, naı̈ve T cells can respond to self antigens or tumor antigens to induce a state of autoimmunity or tumor immunity, respectively. Exploiting these conditions to target unique tumor antigens will enable us to develop better cancer immunotherapies.