It has been well documented that nordihydroguaiaretic acid (NDGA), a phenolic lignan isolated from the creosote bush, Larrea tridentate, has anti-cancer activity in vitro and in vivo. Several mechanisms have been identified that could contribute to these actions, as NDGA directly inhibits metabolic enzymes and receptor tyrosine kinases that are established anti-cancer targets. In the present study, we show that NDGA inhibits the transforming growth factor beta (TGF-beta) type I receptor, a serine threonine kinase receptor. In cultured cells, NDGA treatment repressed Smad2 phosphorylation induced by TGF-beta treatment and by a constitutively active mutant of TGF-beta type I receptor (T202D). NDGA also inhibited downstream transcriptional activation mediated by both TGF-beta treatment and the constitutively active mutant receptor. In vitro, NDGA inhibited TGF-beta type I receptor mediated Smad2 phosphorylation in crude cell lysates and in a purified preparation. Importantly, screening select analogs demonstrated that modification of NDGA's structure resulted in altered potency against the receptor. These results indicated that the structure of NDGA can be modified to achieve increased potency. Together our data provide a novel mechanism for NDGA activity which could help explain its anti-cancer activity, and suggest that NDGA could serve as a structural motif for developing serine/threonine kinase inhibitors with selectivity for TGF-beta type I receptor.