Aim <p>Infectious diseases have significantly contributed to the trajectory of human evolution, serving as influential agents of natural selection and shaping the genetic architecture of immunity and resistance. This review synthesizes key insights from evolutionary biology, genetics, and modern lifestyle studies, highlighting the importance of host–pathogen interactions in human health.</p> Methods <p>A comprehensive literature search was conducted across academic databases, including PubMed, Web of Science, and Scopus, for studies that assert genetic determinants of infectious disease susceptibility, host–pathogen co-evolution, and signatures of natural selection. Evidence from genome-wide association studies (GWAS), whole-genome sequencing, and functional genomics was reviewed to integrate knowledge of host genetic variation and its impact on disease outcomes. Literature on evolutionary mismatch, lifestyle transitions, and their influence on immune-related disorders was also reviewed.</p> Scope and Findings <p>Infectious diseases have historically exercised strong selective pressures on human populations, resulting in adaptive genetic variations, including HLA, CCR5, IFNL3, HBB, and TLR1 gene polymorphisms. These variants offer survival advantages in high-pathogen environments and are evolving due to modern health burdens, resulting in an evolutionary mismatch. Ancestral genotypes are disturbed by reduced exposure to pathogens, changes in diet, and sedentary lifestyles, which intensify vulnerability to autoimmune, metabolic, and inflammatory disorders.</p> Conclusion <p>Understanding the interaction between evolutionary history, host genetics, and contemporary environmental factors is vital for explaining infectious disease susceptibility and resilience. Genomic technologies are providing unparalleled insights into host–pathogen interactions.</p>