Accumulating evidence indicates that psoriasis is a multifactorial disorder caused by the concerted action of multiple disease genes in a single individual, triggered by environmental factors. Some of these genes control the severity of multiple diseases by regulating inflammation and immunity (severity genes), whereas others are unique to psoriasis. Various combinations of these genes can occur even within a single family, accounting in large measure for the many clinical manifestations of psoriasis. The disease-causing variants (alleles) of these genes probably arose early in the history of modern humans. As a result, psoriasis disease alleles are common in the general population, have a worldwide distribution, and often share the same ancestral chromosome with neutral alleles at adjacent loci. This phenomenon, called linkage disequilibrium, explains why psoriasis is strongly associated with HLA-Cw6 worldwide, although HLA-Cw6 is unlikely to be the disease allele. Many unaffected individuals carry 1 or more disease alleles, but lack other genetic and/or environmental factors necessary to produce disease. This explains why psoriasis develops in only about 10% of HLA-Cw6-positive individuals, and why genome-wide linkage scans for psoriasis and other multifactorial genetic disorders have not been uniformly successful. The Human Genome Project is rapidly generating a catalog of human DNA sequence variations. This resource has already allowed precise linkage disequilibrium mapping of the major histocompatibility complex psoriasis gene to just beyond HLA-C, toward HLA-A. This gene is likely to be identified soon. Further development and use of linkage disequilibrium resources will provide a powerful tool for the identification of the remaining psoriasis genes.