We report on the large-scale synthesis of highly oriented ultrathin MoO3 layers using a simple and low-cost atmospheric pressure, van der Waals epitaxy growth on muscovite mica substrates. By this method, we are able to synthesize high quality centimeter-scale MoO3 crystals with thicknesses ranging from 1.4 nm (two layers) up to a few nanometers. The crystals can be easily transferred to an arbitrary substrate (such as SiO2) by a deterministic transfer method and be extensively characterized to demonstrate the high quality of the resulting crystal. We also study the electronic band structure of the material by density functional calculations. Interestingly, the calculations demonstrate that bulk MoO3 has a rather weak electronic interlayer interaction, and thus, it presents a monolayer-like band structure. Finally, we demonstrate the potential of this synthesis method for optoelectronic applications by fabricating large-area field-effect devices (10 μm × 110 μm in lateral dimensions) and find responsivities of 30 mA W–1 for a laser power density of 13 mW cm–2 in the UV region of the spectrum and also as an electron acceptor in a MoS2-based field-effect transistor. ; A.C.-G. acknowledges financial support from the BBVA Foundation through the fellowship “I Convocatoria de Ayudas Fundacion BBVA a Investigadores, Innovadores y Creadores Culturales”, from the MINECO (Ramón y Cajal 2014 program, RYC-2014-01406), and from the MICINN (MAT2014-58399-JIN). A.J.M.-M., G.R.-B., and N.A. acknowledge the support of the MICCINN/MINECO (Spain) through the programs MAT2014-57915-R, BES-2012-057346, and FIS2011-23488; and Comunidad de Madrid (Spain) through the programs NANOBIOMAGNET (s2009/MAT-1726) and S2013/MIT-3007 (MAD2D). J.I. and H.S.J.vdZ. acknowledge the Dutch organization for Fundamental Research on Matter (FOM) and by the Ministry of Education, Culture, and Science (OCW). J.L. and J.F.-R. acknowledge Marie Curie ITN SPINOGRAH (607904-13). F.Y.B. acknowledges financial support from the Swiss National Science Foundation (Ambizione Grant No. PZ00P2_161327). E.M.P. acknowledges financial support from the European Research Council (StG-307609-MINT) and the MINECO of Spain (CTQ2014-60541-P).