Systemic sclerosis (SSc) has a genetic component as demonstrated by familial clustering, by twin studies (showing higher concordance for antinuclear antibody positivity among monozygotic versus dizygotic pairs), and by HLA associations. Identification of the specific genes involved and their mechanism of conferring disease susceptibility or influencing disease expression is under intense study. Several polymorphisms in multiple genes have been put forward as potential candidates but there are discrepancies among some studies. It now appears that the strongest genetic associations are determined by subsetting cases according to autoantibodies. In this review, we will summarize recent studies of candidate gene polymorphisms (including HLA) associated with SSc, which are thought to influence disease susceptibility. In addition, we will review gene expression studies of SSc cultured fibroblasts, intact skin, and peripheral blood to identify common themes among this work. Finally we will highlight future areas of study that will best address deficiencies in our knowledge.