The kinetics of the interaction between T cell receptor (TCR) and major histocompatibility complex (MHC) has an important role in determining thymocyte-positive and -negative selection in the thymus, as well as in T cell activation. The alpha chain of the TCR is the major player in determining how the TCR fits onto the MHC ligand, and thus has a major role in determining whether a T cell develops as class I or class II restricted. In this article, we summarize recent data from our laboratory and others on the role of polymorphism in the Valpha combining site in determining MHC class restriction, and on kinetic parameters in thymocyte selection.