Wnts are a family of secreted glycoproteins that are important in development and cancer. The most common mechanism for Wnt pathway activation in cancer are mutations in β-catenin, causing transcription of known oncogenes such as c-myc. Although increased levels of β-catenin have been reported in NSCLC, activating mutations of β-catenin are rare. Previous studies from our lab demonstrated a Wnt mediated autocrine mechanism causing pathway activation in some NSCLC cell lines. However the Wnt ligands that drive the autocrine loop were unknown. In this study we identified two canonical Wnts, Wnt2 and Wnt3A, over-expressed in two NSCLC cell lines that have autocrine activation. Knocking down the expression of these Wnt ligands using specific shRNA resulted in decreased TCF reporter activity and decreased expression of the universal Wnt target gene Axin2. These results demonstrate over-expression of specific Wnt ligands in NSCLC cells and their contribution to autocrine Wnt pathway activation.