Schwann Cell Precursors (SCPs) are multipotent precursor cells and express SOX10, but relatively little is known about the specification and molecular make-up of human SCPs. To address this, we subjected a human SOX10 knock-in reporter iPSC line to a one step cranial Schwann cell precursor differentiation protocol. We show that SOX10-expressing cells acquire the morphology, motility and gene expression of SCP-like cells, and we exemplify that these cells migrate to multiple developing craniofacial structures following injection into early mouse embryos. We next defined the bulk and single-cell transcriptomes, metabolomes, and proteomes of SOX10 expressing human SCP-like cells, revealing gene expression heterogeneity, shifts in splicing events, a reduced dependence on glycolysis, and changes in the expression of cell adhesion proteins, miRNAs and LncRNAs that accompany SCP specification. Discovery proteomics identifies MCAM (CD146) as a cell surface marker that permits the isolation of pure SOX10 expressing human cranial SCP-like cells from human pluripotent stem cell lines subjected to SCP differentiation. We further show that this permits isolation of Down syndrome cranial SCP-like cells that display defects in proliferation. Collectively these data provide a detailed map of the molecular make-up of in vitro generated human cranial Schwann cell precursor-like cells and exemplify the utility of MCAM-sorted cranial SCP-like cells for modelling human neurocristopathies.