The transforming growth factor-β (TGF-β) family plays major pleiotropic roles by 
regulating many physiological processes in development and tissue homeostasis. 
The TGF-β signaling pathway outcome relies on the control of the spatial and 
temporal expression of >500 genes, which depend on the functions of the Smad 
protein along with those of diverse modulators of this signaling pathway, such 
as transcriptional factors and cofactors. Ski (Sloan-Kettering Institute) and 
SnoN (Ski novel) are Smad-interacting proteins that negatively regulate the 
TGF-β signaling pathway by disrupting the formation of R-Smad/Smad4 complexes, 
as well as by inhibiting Smad association with the p300/CBP coactivators. The 
Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone 
deacetylases to repress gene transcription. The TGF-β/Smad pathway and 
coregulators Ski and SnoN clearly regulate each other through several positive 
and negative feedback mechanisms. Thus, these cross-regulatory processes finely 
modify the TGF-β signaling outcome as they control the magnitude and duration of 
the TGF-β signals. As a result, any alteration in these regulatory mechanisms 
may lead to disease development. Therefore, the design of targeted therapies to 
exert tight control of the levels of negative modulators of the TGF-β pathway, 
such as Ski and SnoN, is critical to restore cell homeostasis under the specific 
pathological conditions in which these cofactors are deregulated, such as 
fibrosis and cancer.