Effector T cells leave the lymph nodes armed with specialized functional attributes. Their antigenic targets may be located anywhere in the body, posing the ultimate challenge: how to efficiently identify the target tissue, navigate through a complex tissue matrix and, ultimately, locate the immunological insult. Recent advances in real-time in situ imaging of effector T cell migratory behaviour have revealed a great degree of mechanistic plasticity that enables effector T cells to push and squeeze their way through inflamed tissues. This process is shaped by an array of ‘stop’ and ‘go’ guidance signals including target antigens, chemokines, integrin ligands and the mechanical cues of the inflamed microenvironment. Effector T cells must sense and interpret these competing signals to correctly position themselves to mediate their effector functions for complete and durable responses in infectious disease and malignancy. Tuning T cell migration therapeutically will require a new understanding of this complex decision-making process.