T-lymphocyte activation through the T cell antigen receptor (TCR) is a central event in adaptive immunity. Yet almost three decades after the discovery of its molecular components, the mechanism of TCR “triggering” is still unknown. This is due in large part to the complexity of the receptor and to a lack of structural information on the intact complex. In order to form a functional, surface-expressed receptor, the ligand-sensing TCRαβ heterodimer must assemble with CD3εγ, CD3εδ and ζζ signal-transducing modules. The precise spatial arrangement of these four dimeric modules is not known, but predictions about their relative positions figure prominently in models of receptor activation. The best-characterised interactions governing TCR-CD3 assembly are buried within the lipid bilayer: three basic amino acids in the transmembrane (TM) domains of TCRαβ guide association of the three signalling modules through acidic and hydroxyl-bearing residues in their TM domains. The disposition of these key basic residues should therefore reveal the positions of CD3 and ζζ dimers around the central TCR “hub.” However, little is known about the proximity and orientation of TCR α and β TM domains, or indeed whether a specific interface exists at all. We are using a cysteine scanning approach to map points of contact among TCR and CD3 subunits in the context of an assembled, membrane-embedded complex. Our results so far reveal that TCRα and β TM domains are closely associated and identify several contacts within a specific helix-helix interface. These observations are guiding our solution NMR-based efforts to determine a detailed structure of the TCRαβ TM domain complex and precisely map the arrangement of signalling modules around the receptor. Our aim is to produce a comprehensive TM model that will aide in understanding how these components cooperate to transmit the crucial signals that activate T cells.