Moyamoya disease is a rare cerebrovascular disorder characterized by progressive stenosis of large intracranial arteries and a secondary compensatory network of vulnerable collaterals. While the underlying molecular mechanisms remain unclear, both genetic and immune factors have been implicated, calling for a multiomics approach to study the complex pathogenesis of the disease. We performed whole exosome sequencing and plasma proteomics on a cohort of twelve patients with well-documented moyamoya angiopathy. In addition, we conducted an in-depth single cell spatial proteomics analysis on an occluded artery retrieved post-mortem from one idiopathic patient. Variants in the major susceptibility gene RNF213 were found in three patients, while five patients had other underlying genetic conditions, including trisomy 21 and pathogenic variants in ACTA2, SAMHD1 and NFIA. Plasma proteomics revealed cellular fibronectin as a potential biomarker for moyamoya disease, while artery spatial proteomics profiling showed extensive vascular smooth muscle cell infiltration in the intima associated with phenotypic switching. Moreover, infiltration of macrophages and antigen-presenting cells points to a role for inflammatory signals in disease progression. Together, our study supports a multiomics approach to unravel the complex pathogenesis of moyamoya disease, demonstrating the relevance of genetic and immune triggers in vascular remodeling and moyamoya disease development.