The inflammatory T-cell response is important for protecting the host against infections and tumors. However, dysregulated generation of effector T cells produces high levels of inflammatory cytokines and cytotoxic molecules and may cause inflammatory disorders, such as chronic infections, autoimmune diseases and graft-versus-host disease after allogeneic bone marrow transplantation. Thus, tight regulation of effector T cells is essential. Accumulating evidence indicates that Notch plays critical roles in regulating the differentiation of antigen activated T cells into distinct lineages of effector T cells. Furthermore, significant progress has been made in the development of new methods in order to modulate Notch for disease treatment. In this article, we will discuss recent findings that help to gain insight into the impact of Notch in the regulation of effector T cells and highlight the beneficial effects of modulating Notch in inflammatory diseases