Activated T helper cells produce many cytokines, some of which are secreted through the immunological synapse toward the antigen-presenting cell. Here we have used immunocytochemistry, live-cell imaging and a surface-mediated secretion assay to show that there are two cytokine export pathways in T helper cells. Some cytokines, including interleukin 2 and interferon-gamma, were secreted into the synapse, whereas others, including tumor necrosis factor and the chemokine CCL3 (MIP-1alpha), were released multidirectionally. Each secretion pathway was associated with different trafficking proteins, indicating that they are molecularly distinct processes. These data suggest that T helper cells release some cytokines into the immunological synapse to impart specific communication and others multidirectionally to promote inflammation and to establish chemokine gradients.