Non-syndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect. Genetic and environmental factors have been causally implicated and studies have begun to delineate genetic contributions. The Wnt genes are involved in regulating mid-face development and upper lip fusion and are therefore strong candidates for an etiological role in NSCLP. Furthermore, the clf1 region in A/WyN clefting susceptible mice contains the Wnt3 and Wnt9B genes. To assess the role of the Wnt family of genes in NSCLP, we interrogated seven Wnt genes (Wnt3, Wnt3A, Wnt5A, Wnt7A, Wnt8A, Wnt9B and Wnt11) in our well-defined NSCLP dataset. Thirty-eight single nucleotide polymorphisms were genotyped in 132 multiplex NSCLP families and 354 simplex parent-child trios. In the entire dataset, single-nucleotide polymorphisms (SNPs) in three genes, Wnt3A (P = 0.006), Wnt 5A (P = 0.002) and Wnt11 (P = 0.0001) were significantly associated with NSCLP after correction for multiple testing. When stratified by ethnicity, the strongest associations were found for SNPs in Wnt3A (P = 0.0007), Wnt11 (P = 0.0012) and Wnt8A (P = 0.0013). Multiple haplotypes in Wnt genes were associated with NSCLP, and gene-gene interactions were observed between Wnt3A and both Wnt3 and Wnt5A (P = 0.004 and P = 0.039, respectively). This data suggests that alteration in Wnt gene function may perturb formation and/or fusion of the facial processes and predispose to NSCLP.