The ability of lymphocyte receptor V, D and J gene segments to rearrange generates much of the receptor diversity that is the hallmark of the immune system. Naturally, the mechanisms of immunoglobulin and T-cell receptor gene recombination are of enormous interest. Here, Fred Alt and colleagues review current understanding of the process and speculate on future findings.

The mechanism of VDJ recombination and the manner in which this site-specific recombination activity is controlled has remained a difficult topic to study directly. The major difficulty stems from the inability to identify the components of VDJ recombinase and to reproduce this reaction in a cell-free system. Likewise, the nature of elements that control the tissue and stage specificity of the reaction has remained somewhat controversial, primarily because of the paucity of readily manipulable systems that allow the normal physiological constraints on this activity to be unequivocally identified. Lately, however, there have been significant advances in both of these areas that may allow resolution of the VDJ recombination process in great detail.