The regulated secretion of cellular proteins is central to the correct function of many cell types, including immune cells. Lymphocyte control of the storage, transport and exocytosis of immunomodulatory molecules is a highly specialised task triggered by T cell receptor engagement. The regulated secretory pathway in CD8+ T and NK cells has been the focus of much research, and recent advances have provided insight into the molecular mechanisms governing secretory organelle biogenesis, trafficking and killing. By contrast, regulated secretory pathways in CD4+ T cells have not been studied extensively. Aside from their physiological function in normal T cells, components of CD4+ T cell secretory pathways might be implicated in the assembly of HIV-1. Here, we review findings that shed light on CD4+ T cell secretion in health and disease.