It is becoming evident that several genetic factors participate in modulating susceptibility to SSc and its clinical manifestations. Some genes that specifically affect ECM metabolism and vascular function may be unique to SSc and scleroderma-related disorders; others, such as those genes involved in regulating immune tolerance, are likely shared with other autoimmune diseases. The effect of genetic variations (or polymorphisms) that are found in most of these genes taken individually will likely have only a small or modest effect on disease risk; only a few genetic variations are expected to be highly penetrant. Moreover, genetic studies in SSc have to deal with the additional issues of heterogeneous phenotypes, low disease prevalence in the general population, and an even greater paucity of multiplex families that makes traditional linkage studies difficult, if not impossible. Alternative approaches include allelic association studies, but conventional case-controls designs may be subject to selection bias and will require large sample sizes if the genes that are under investigation confer only modest (OR = 1.5-2.0) disease risk (Fig. 2). The simultaneous examination of several genes that are biologically relevant to a specific disease process to attain higher aggregate ORs, is one approach that was used in several reports that were cited in this review. The use of family-based controls, such as in the transmission-disequilibrium test (based on assessment of the transmitted or nontransmitted alleles that are associated with disease from heterozygous parents to affected offspring), would provide more robustness to spurious associations from population stratification, but is actually less powerful and efficient than case-control designs. Furthermore, for many late adult-onset diseases the effort required to obtain samples from living parents are for a variety of reasons not trivial. The success of these allelic association-based approaches depends on the identification of likely candidate disease genes (or at least markers in disequilibrium with disease genes), careful definition/ascertainment of disease phenotypes to minimize genetic heterogeneity, and for case-control designs, strategies to account for population stratification or admixture. The identification of candidate genes will be aided by rapid progress in the Human Genome Project and other genome efforts that will eventually identify all human genetic variations. Although this will lead to better understanding of the genes that might be involved in complex diseases, much work is required to understand the basic biology of how disease genotypes become clinical phenotypes. This is especially daunting in complex diseases, such as SSc, where the phenotype (including disease susceptibility and clinical presentation) is influenced by dynamic interactions between genetic variations and environment. Multi-center collaborative efforts with research paradigms that integrate genetic and environmental factors (including sociodemographic variables) will be required to elucidate the contribution of environment and genetics in the pathogenesis of SSc.