The T-cell receptor (TCR) complexes are highly intricate multiprotein cell surface receptors that play a crucial role in the immune system ofT cells. Signaling mediated by these receptor complexes is essential for determining the fate of T cells, initiating immune responses mediated by T cells, and facilitating the differentiation of T cells into distinct functional effector and memory populations. Despite their pivotal func- tions, the mechanism of organization and activation of these complexes have remained elusive. In this presentation, we discuss the structure of the human TCR-CD3 complex, which provides a long-awaited resolution to questions surround- ing the assembly and activation mechanisms of the TCR-CD3 complex. Specifically, two cholesterol molecules act as a latch, binding to the complex formed by the trans- membrane regions of TCR-CD3. This interaction locks the CD3ζ subunit into an inac- tive conformation within the membrane. This finding is further supported by struc- ture-based mutagenesis experiments. Furthermore, a detailed analysis of the first constitutively active TCR-CD3 structure reveals conformational changes in the trans- membrane segment of the intact TCR-CD3 complex. This not only clarifies the long-standing question of whether conformational changes occur in the transmem- brane segments during TCR triggering but also demonstrates the coupling ofthe TCR triggering process to the conformation of the complex formed by the transmembrane regions. These structural findings also present new opportunities for the develop- ment of innovative therapies that target the TCR-CD3 complex, with potential appli- cations in anti-cancer and anti-autoimmunity treatments.