A fundamental question in developmental immunology is how bipotential thymocyte 
precursors generate both CD4+ helper and CD8+ cytotoxic T cell lineages. The MHC 
specificity of αβ T cell receptors (TCRs) on precursors is closely correlated 
with cell fate-determining processes, prompting studies to characterize how 
variations in TCR signaling are linked with genetic programs establishing 
lineage-specific gene expression signatures, such as exclusive CD4 or CD8 
expression. The key transcription factors ThPOK and Runx3 have been identified 
as mediating development of helper and cytotoxic T cell lineages, respectively. 
Together with increasing knowledge of epigenetic regulators, these findings have 
advanced our understanding of the transcription factor network regulating the 
CD4/CD8 dichotomy. It has also become apparent that CD4+ T cells retain 
developmental plasticity, allowing them to acquire cytotoxic activity in the 
periphery. Despite such advances, further studies are necessary to identify the 
molecular links between TCR signaling and the nuclear machinery regulating 
expression of ThPOK and Runx3.