The elimination of pathogens and pathogen-infected cells initially rests on the rapid deployment of innate immune defences. Should these defences fail, it is the lymphocytes--T cells and B cells--with their antigen-specific receptors that must rise to the task of providing adaptive immunity. Technological advances are now allowing immunologists to correlate data obtained in vitro with in vivo functions. A better understanding of T-cell activation in vivo could lead to more effective strategies for the treatment and prevention of infectious and autoimmmune diseases.