The accelerating progress in multi-omics and evolutionary biology is transforming our understanding of how genomes evolve and innovate at the molecular level. This Special Issue, Genome Evolution and Molecular Innovation: Implications for Drug Resistance and Disease Mechanisms, aims to highlight cutting-edge research that links evolutionary processes with biomedical outcomes. We invite studies that integrate genomics, transcriptomics, proteomics, and metabolomics to uncover how genetic variation, gene regulation, and molecular adaptation shape disease pathways and therapeutic responses. Topics of interest include, but are not limited to, the evolution of drug resistance, regulatory network rewiring, mutation–selection balance, convergent molecular innovations, and host–pathogen coevolution. By bridging evolutionary theory and biomedical application, this Special Issue seeks to illuminate the mechanisms by which genome dynamics drive molecular diversity, influence disease susceptibility, and inspire the next generation of precision medicine and drug discovery.