The cytoplasmic β-catenin protein is implicated as a cell-cell adhesion regulator coupled with cadherin and is considered as a member in the wingless/Wnt signal transduction pathway. Mutations in CTNNB1, the gene encoding β-catenin, tend to impact or even eliminate APC-dependent serine and threonine phosphorylation sites in exon 3, resulting in oncogenic stabilization of the protein. Increased protein within the nuclei serves as a transcriptional factor through binding to the Tcf/Lef family. Mutations in the β-catenin gene are uncommon in NSCLC occurring in about 1-4% of the cases. Nuclear accumulation of β-catenin was found to be associated with EGFR mutations, and β-catenin overexpression was associated with NSCLC cell line resistance to gefitinib. Wnt pathway inhibitors are in preclinical development or have entered early clinical trials. Because high β-catenin expression has been associated with good outcome rather than with poor outcome in NSCLC patients, it could potentially prove important to target specific downstream β-catenin functions rather than using agents that could directly suppress β-catenin levels through upstream targeting of the Wnt pathway.