The European Alps show a high degree of endemism associated mainly with the location of glacial refugia and environmental heterogeneity. Several Alpine endemics have evolved in the genus Alyssum. Here we study perennial Alyssum populations in the Western Alps, mainly distributed in the Aosta Valley region, which hosts high species diversity, although endemics are rare. We addressed the recently described stenoendemic A. rossetii and taxonomically uncertain populations usually attributed to A. montanum s.s. to clarify their phylogenetic position and morphological differentiation. The latter entity has been shown to be distinct from A. montanum s.s. and is described as a new species, Alyssum cognense, phylogenetically placed in the A. montanum–A. repens species complex. Both morphological and genetic patterns revealed that its closest relative occurs in the central Balkans. We present detailed ecological characteristics and morphological differentiation of A. cognense sp. nov. from its relatives and geographically closest species and speculate on its biogeographic origin. Genetic patterns (reduced diversity and nestedness) suggest long-distance dispersal from the central Balkan Peninsula. The second studied species, A. rossetii, is phylogenetically distant and belongs to the mainly Asian Alyssum section Gamosepalum lineage, which includes few representatives in southern and eastern Europe. The phylogenetically closest species of A. rossetii are Anatolian endemics, so this extreme disjunction remains puzzling. The present study illustrates the need for in-depth taxonomic and phylogenetic studies, even in well-explored Alpine regions, and also shows that the processes underlying the evolution of endemics can be complex and poorly understood.