The ten eleven translocation (Tet) family of proteins includes three members (Tet1-3), all of which have the capacity to convert 5-methylcytosine to 5-hydroxymethylcytosine in a 2-oxoglutarate- and Fe(II)-dependent manner. Tet1 and Tet2 are highly expressed in undifferentiated embryonic stem cells (ESCs), and this expression decreases upon differentiation. Notably, the expression patterns of Tet1 and Tet2 in ESCs parallels that of pluripotency genes. To date, however, the mechanisms underlying the regulation of Tet gene expression in ESCs remain largely unexplored. Here we report that the pluripotency transcription factor, Oct4, directly regulates the expression of Tet2. Using RNAi, real time quantitative PCR, dual-luciferase reporter assays and electrophoretic mobility shift assays, we show that Oct4 promotes Tet2 transcription by binding to consensus sites in the proximal promoter region. Furthermore, we explored the role of the small molecule inhibitor, SC1 (pluripotin) on Tet gene expression. We show that SC1 promotes Tet3 expression, but represses Tet1 and Tet2 expression. Our findings indicate that Tet2 are crucial downstream targets of the pluripotency factor Oct4, and highlight a role for Oct4 in the regulation of DNA methylation in ESCs. In addition, these findings also provide a new insight into drug-mediated gene regulation.