Endothelin-1 (EDN1) is a growth factor that is frequently produced by cancer cells and plays a critical role in tumorigenesis. However, the molecular mechanism controlling the expression of EDN1 in cancers is unknown. Constitutive activation of β-catenin pathway is responsible for the initiation of the vast majority of colon cancers. Here we show that the EDN1 gene is directly regulated by β-catenin in colon cancer cells. A specific DNA element within the EDN1 promoter is required for activation, and is associated with β-catenin's cognate DNA binding partner, TCF4, in vivo. Inhibition of β-catenin signaling results in lowered expression of EDN1, while enhancement of β-catenin signaling leads to further activation of the gene. Significantly elevated EDN1 expression occurs in 80% of primary human colon cancers, consistent with it being a direct target of β-catenin. Furthermore, EDN1 is able to rescue colon cancer cells from growth arrest and apoptosis resulting from inhibition of β-catenin signaling, implicating a key role of EDN1 in promoting the oncogenic function of β-catenin. These results indicate EDN1 overexpression as a major cause in colon cancers and reveal further details of the genetic programs responsible for tumorigenesis of colon cancers.