In spite of the evolutionary interest and economic importance of the grape genus Vitis, the phylogenetic relationships and drivers of species diversification remain poorly understood. Previous studies on North American Vitis in the last decade have detected strong cytonuclear discordances. Further phylogenomic analyses are needed to unravel phylogenetic relationships and explore hybridization events, especially in several North American species complexes. The Vitis cinerea species complex (VCC) is morphologically highly polymorphic. Several studies recognized four varieties in the complex, and these varieties have recently been treated at the species level as V. baileyana, V. berlandieri, V. cinerea and V. simpsonii. However, integrated analyses with an enhanced sampling of the V. cinerea complex including contact zones/areas of sympatry are needed to clarify hybridization events and explore drivers of diversification in this complex. In this study, samples of the Vitis cinerea complex across its distributional range were broadly collected with all four varieties included. Major clades and relationships of the species complex have been assessed in a broad phylogenetic framework of North American Vitis, using newly developed baits for Vitaceae with 1013 nuclear genes. Hybridization events have been tested in the species complex to aid in the species delimitations. Ecological niche modeling and principal component analysis (PCA) of the environmental variables were used to assess ecological differentiation in the diversification of VCC. Our results support the recognition of four species (V. baileyana, V. berlandieri, V. cinerea and V. simpsonii) in the VCC, and showcase the interactions of geographic isolation, ecological differentiation and hybridization in driving the processes of species differentiation.