Even though DNA methylation is known to be correlated with gene repression, it has never been demonstrated that this modification must indeed be removed from a gene in order for it to become activated during cell differentiation in vivo. In this paper, we inactivated the enzymes responsible for the demethylation reaction in the B-cell lineage and in this manner have shown that this epigenetic mark plays a critical role in development, independently of the many specific transcription factors that direct the selection of genes involved in cell differentiation. Our study is the first to our knowledge to causally connect all of the molecular components necessary to prove the link between the Tet enzymes, CpG demethylation, expression, and phenotype.