Over the past four years, pivotal discoveries have deepened the understanding of the relationship between genetic factors and SARS-CoV-2 infection. Numerous genes associated with severe COVID-19 suggest a potential genetic predisposition, which may help explain why some individuals develop more serious illnesses. Emerging evidence highlights the role of genes involved in pulmonary immunity, such as Forkhead box Protein P4 (FOXP4), whose increased expression in lung tissue has been linked to more severe disease. Other genes - Transmembrane Protease Serine-2 (TMPRSS2), Leucine Zipper Transcription Factor Like-1 (LZTFL1), Solute Carrier family 6 member 20 (SLC6A20), Tyrosine Kinase-2 (TYK2), Angiotensin-Converting Enzyme (ACE), and FYVE and Coiled-Coil Domain-Containing-1 (FYCO1) - have also been implicated in COVID-19 severity. In contrast, certain genetic variants - such as the T-allele of rs12329760 in the TMPRSS2 gene and rs35705950-T in the Mucin-5B (MUC5B) gene - may confer protection against severe disease. Overall, the evidence suggests that genetic factors can influence both susceptibility to and protection from severe COVID-19, although these associations are likely shaped by complex interactions with environmental, behavioral, and other biological factors. This review summarizes current knowledge on genetic determinants linked to COVID-19 outcomes.