Epistasis or modifier genes, that is, gene-gene interactions of non-allelic partners, play a major role in susceptibility to common human diseases. This old genetic concept has experienced a major renaissance recently. Interestingly, epistatic genes can make the disease less severe, or make it more severe. Hence, most diseases are of different intensities in different individuals and in different ethnicities. This phenomenon affects sickle-cell anemia carriers and other hemoglobinopathies, systemic lupus erythematosus, cystic fibrosis, complex autoimmune diseases, venous thromboembolism, and many others. It is likely, and fortunate, than 20 years form now, patients entering a medical facility will be subjected to a genomic scanning, including pathogenic genes as well as epistatic genes.