Genomic instability (GIN), an increased tendency to acquire genomic alterations, is a cancer hallmark. However, its frequency, underlying causes, and disease relevance vary across different cancers. Multiple myeloma (MM), a plasma cell malignancy, evolves through premalignant phases characterized by genomic abnormalities. Next-generation sequencing (NGS) methods are deconstructing the genomic landscape of MM across the continuum of its development, inextricably linking malignant transformation and disease progression with increasing acquisition of genomic alterations, and illuminating the mechanisms that generate these alterations. Although GIN drives disease evolution, it also creates vulnerabilities such as dependencies on 'superfluous' repair mechanisms and the induction of tumor-specific antigens that can be targeted. We review the mechanisms of GIN in MM, the associated vulnerabilities, and therapeutic targeting strategies.