The role of a key Wnt coreceptor Lrp6 during heart development remains unclear. Here we show that ablation of Lrp6 in mice causes conotruncal anomalies including double-outlet right ventricle (DORV), outflow tract (OFT) cushion hypoplasia, and ventricular septal defect (VSD). Cardiac neural crest cells are specifically lost in the dorsal neural tube and caudal pharyngeal arches of the mutant embryos. We also demonstrate that Lrp6 is required for proliferation and survival of cardiac progenitors and for the expression of Isl1 in the secondary heart field. Other known cardiogenic regulators such as Msx1, Msx2, and Fgf8 are also significantly diminished in the mutant pharyngeal arches and/or OFT. Unexpectedly, the myocardium differentiation factors Mef2c and Myocardin are upregulated in the mutant OFT. Our results indicate that Lrp6 is essential for cardiac neural crest and OFT development upstream of multiple important cardiogenic genes in different cardiac lineage cells during early cardiogenesis. Developmental Dynamics 239:200–210, 2010. © 2009 Wiley-Liss, Inc.