Epigenetic gene inactivation in mammalian cells involves many silencing mechanisms. One of these mechanisms is the transcriptional repression by targeted promoter hypermethylation. However, the molecular mechanisms involved in the site-specific DNA (hyper)methylation are not fully elucidate. By using the Dnmt3a/c-myc interaction as an example, we here showed that this interaction promotes the site-specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Indeed, the invalidation of c-myc reveals that c-myc allows the Dnmt3a recruitment on c-myc box of c-myc-regulated genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. Indeed, our work indicates that Dnmt3a and Dnmt3b have consensus sequences to methylate DNA (T/A/C)(A/T)(T/G/A)CG(T/G/C)G(G/C/A) and (A/C)(C/G/A)(A/G)CGT(C/G)(A/G). Thus, the low specificity of these sequences (consensual for 162 and 48 possibilities, respectively) does not support the idea of targeted DNA methylation. By monitoring transcription factor arrays spotted with 103 transcription factors, we next identified 42 transcription factors interacting with Dnmt3a and Dnmt3b (such as CREB and FOS), 27 transcription factors interacting with Dnmt3a (such as AP2alpha and p53), 10 transcription factors interacting with Dnmt3b (such as SP1 and SP4) and 24 transcription factors devoid of direct interaction with Dnm3a and Dnmt3b (such as C/EBPalpha and NFkappaB-p65). Thus, The description of direct interaction between Dnmt3a and/or Dnmt3b and transcription factors provides rational molecular explanation to the mechanisms of targeted DNA (hyper)methylation, and to the mechanisms by which transcription factors repress genes expression.