A better understanding of the allelic structure of common human disease loci may help identification of the responsible genes, and is thus a topic of considerable practical importance. If few alleles at each locus account for the majority of disease risk, then screening for these causative factors will be greatly simplified. In contrast, if large numbers of independent alleles are responsible, dramatic improvements in genotyping speed will be necessary, placing the dream of personalized medicine far in the future. In this review, the evidence for and against the optimistic and pessimistic viewpoints is discussed. It appears that neither position has been proved or disproved, but the available evidence indicates that common diseases are due at least in part to genes with a small number of disease-associated alleles.