T-cells are thought to play important roles in the coordination and development of immune responses in both health and disease. A key checkpoint in the prevention of inappropriate activation of T-cells is the requirement for costimulation by professional APCs via receptors such as CD28. Several in vivo and in vitro methods of experimental anergy induction have been developed and are in popular use today. However, the biochemical events that determine Tcell fate following the application of activating vs. anergizing stimuli remain poorly understood. We present a survey of T-cell signal transduction in productive encounters with antigen-presenting cells, as well as the molecular mechanisms that are thought to alter these signaling pathways in T-cell anergy and the conceptual and experimental context in which this understanding has been developed. A strong possibility is that the program of anergy induction involves the upregulation of one or more anergy factors and over the years, several possible mechanisms of T-cell anergy have been proposed. Amongst these, E3 ubiquitin ligases such as Cbl-b, Itch and GRAIL have recently emerged as being essential players in T-cell tolerance, as well as host survival.