Rheumatology deals with many different entities among which dys/autoimmune diseases occupy a position of preponderance. This review focuses on the concept of complex genetic disease, which is illustrated by three different chronic inflammatory joint diseases: rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Genetic studies have established that a common genetic background is shared by many autoimmune disorders. Interestingly, although common genetic factors are shared by diseases that produce different phenotypes, risk variants can exert a strong influence on the phenotype of a given disease. Genetics cannot fully explain the determinism of complex genetic diseases. Future genetic studies must incorporate data on exposure to potential environmental factors. The next step in unravelling complex genetic diseases will involve investigations not only of gene–gene and gene–environment interactions, but also of epigenetics, defined as transmissible and reversible changes in gene expression that are not related to changes in the DNA sequence. The past decade has witnessed an impressive accumulation of data on the determinism of complex diseases, and the next will probably bring further insights into the pathophysiology of dys/autoimmune diseases.