Understanding genomic organization and its functional characteristics, which directly or indirectly contributes to an organism’s adaptability, is an essential aspect of evolution, speciation, biodiversity, and ecophysiology. In mulberry (Morus spp.), the evolution of chromosome size, number, structure, DNA composition, polyploidization (or whole genome duplication), intraspecific hybridization, and expansion of transposable elements indicate the remarkable plasticity of nuclear genomes in adaptation. The genus Morus exhibits a wide range of species diversity, with a significant cytotype variation, including diploid (2n = 2x = 28), triploid (2n = 3x = 42), tetraploid (2n = 4x = 56), hexaploid (2n = 6x = 84), and 22-ploid (2n = 22x = 308) across fourteen Asian and three New World species. Despite the primary focus on mulberry crops, a comprehensive understanding of diversity and its ecophysiological implications remains lacking, hindering the development of strategies for systematic improvement and conservation against global climate change. In this chapter, we focus on evolutionary aspects, native biomes, and the ecophysiology of mulberry. Moreover, polyploid-specific reduced growth superiority, adaptability, and genome downsizing have been emphasized in different climate scenarios. Furthermore, we have emphasized an in-depth state-of-the-art multi-omics approach to comprehend and mitigate climate-related challenges in Morus spp. The overall study highlights an urgent need to understand the genetic basis of polyploid and ploidy-associated traits for effective conservation of mulberry.