The vast majority of peripheral T cells exist as resting lymphocytes until a signal for activation has been received. In response to antigen, this activation involves ligation of the T-cell receptor (TCR) and signal transmission through the CD3 complex, which then initiates a cascade of intracellular events that lead to the expression of genes used in T-cell activation. T-cell activation also requires soluble mediators in the form of cytokines and chemokines that regulate the process in both positive and negative ways, and costimulatory signals received in conjunction with TCR/CD3 signaling are important in the activation of T cells. Unlike T cells in other peripheral immune compartments, small and large intestinal intraepithelial lymphocytes (IELs) bear some but not all properties of activated T cells, suggesting that they constitute a large population of 'partially activated' effector cells. Thus, regulation of the IEL activation process must be held in tight check, yet it must be ready to respond to foreign antigen rapidly and effectively. We discuss how costimulatory molecules may hold the key to controlling IEL activation through a multiphase process beginning with cells that have already entered into the early stage of activation.