Understanding the intercellular and intracellular mechanisms that maintain anergy and prevent the induction of full effector function is one avenue that may allow us to manipulate immune responses. Recent studies of T cell receptor (TCR)-proximal signaling events in different models of T cell unresponsiveness have suggested that biochemically distinct forms of anergy may exist in vivo. T cell responsiveness can be altered through the control of the intracellular pool of key second messengers, such as diacylglycerol (DAG) or the lipid modification of signaling molecules, such as the Linker for activated T cells (LAT). Studies on the molecule programmed death-1 (PD-1) and its ligands have revealed that tissue-resident signals are essential in the maintenance of T cell unresponsiveness. Thus, the emerging view is that T cell anergy is a dynamic state whose establishment and maintenance can be influenced by numerous different signaling pathways.