Ski and SnoN are two proto-oncogenes that, at high cellular concentrations, are associated with tumors. Up to now, apart the fact that SnoN and Ski were known to bind to DNA indirectly, very little was known about the mechanism which enables these factors to induce tumorigenesis. We know now that SnoN and Ski interact with the SMAD proteins which are mediators of TGFbeta signaling. These SMADs enable recruitment to target gene promoters of SnoN and Ski as well as the histone deacetylase activity which is associated with them. Whereas physiologic concentrations of SnoN and Ski allow a feedback regulation of TGFbeta signaling, deregulation of SnoN or Ski expression leads to total inhibition of TGFbeta signaling and of the tumor suppressors Smad2 and Smad4, which can explain the role of SnoN and Ski as oncogenes.