<i>Objectives:</i> Non-syndromic orofacial clefts, i.e. cleft lip (CL) and cleft palate (CP), are among the most common birth defects. The goal of this study was to identify genomic regions and genes for CL with or without CP (CL/P). <i>Methods:</i> We performed linkage analyses of a 10 cM genome scan in 820 multiplex CL/P families (6,565 individuals). Significant linkage results were followed by association analyses of 1,476 SNPs in candidate genes and regions, utilizing a weighted false discovery rate (wFDR) approach to control for multiple testing and incorporate the genome scan results. <i>Results:</i> Significant (multipoint HLOD ≥3.2) or genome-wide-significant (HLOD ≥4.02) linkage results were found for regions 1q32, 2p13, 3q27-28, 9q21, 12p11, 14q21-24 and 16q24. SNPs in <i>IRF6</i> (1q32) and in or near <i>FOXE1</i> (9q21) reached formal genome-wide wFDR-adjusted significance. Further, results were phenotype dependent in that the <i>IRF6</i> region results were most significant for families in which affected individuals have CL alone, and the <i>FOXE1</i> region results were most significant in families in which some or all of the affected individuals have CL with CP. <i>Conclusions:</i> These results highlight the importance of careful phenotypic delineation in large samples of families for genetic analyses of complex, heterogeneous traits such as CL/P.