In modern biology, comparative genomic analysis of genetic sequences across species has become an essential tool for understanding and treating human diseases. This approach utilizes genome sequencing and bioinformatics to unravel the intricate genetic basis of disease. This has been key to pinpointing conserved genes and pathways that are central to disease processes. Evolutionary genomics provides further insight by tracing changes in genomes over time. This perspective elucidates how certain genetic disorders have developed over time and why some species are more prone to certain diseases. Moreover, advanced sequencing has enabled the comparison of large genomic segments (syntenic regions) between species. This has been instrumental in inferring functional equivalencies and elucidating genetic causes of diseases heavily reliant on animal models, like autoimmune disorders. In summary, we will utilize comparative genomic tools together with classical genetics to identify genes influencing variation in complex diseases. By integrating data from multiple genomes and evolutionary histories, this field holds promise for discovering new therapeutic targets and enhancing our molecular understanding of disease mechanisms. We propose omics can contribute to these goals but also discuss core opportunities and challenges (Clark, M. S., Hoffman, et al. (2023). Multi-omics for studying and understanding polar life. Nature Communications, 14(1)). As sequencing continues to progress, the potential for transformative discoveries in disease research through comparative and evolutionary genomics remains immense and largely untapped.