The transcription factor ThPOK is necessary and sufficient to trigger adoption of the CD4 lymphocyte fate. Here we investigate the regulation of ThPOK expression and its subsequent control of CD4+ T cell commitment. Treatment of immature thymocytes with anti-TCR (T cell receptor) showed that TCR signals were important in ThPOK induction and that the CD4+8lo stage was the likely target of the inductive TCR signal. We identified at the ThPOK locus a key distal regulatory element (DRE) that mediated its differential expression in class I- versus II-restricted CD4+8lo thymocytes. The DRE was both necessary for suppression of ThPOK expression in class I-restricted thymocytes and sufficient for its induction in class II-restricted thymocytes. Mutagenesis analysis defined an essential 80bp core DRE sequence and its potential regulatory motifs. We propose a silencer-dependent model of lineage choice, whereby inactivation of the DRE silencer by a strong TCR signal leads to CD4 commitment, whereas continued silencer activity leads to CD8 commitment.