The transmembrane protein tapasin has an essential role in the assembly of stable major histocompatibility (MHC) class I/peptide complexes. Within the endoplasmic reticulum, tapasin associates with both the transporter associated with antigen processing (TAP) and the MHC class I molecule. The tapasin/TAP association has been clearly shown to involve the transmembrane domains (TMDs) of both molecules and to result in the stable expression of TAP. Although the influence of tapasin on MHC class I molecule folding and surface expression has been extensively studied, relatively little is known at the structural level regarding the interaction between tapasin and the MHC class I molecule. Here we summarize our current understanding of functions involving the tapasin TMD and propose that, beyond stabilizing TAP, the tapasin TMD may also interact with the MHC class I heavy chain.