Complex diseases can involve the interaction of multiple genes and environmental factors. Discovering these genes is difficult, and in silico based strategies can significantly improve their detection. Data mining and automated tracking of new knowledge facilitate locus mapping. At the gene search stage, in silico prioritization of candidate genes plays an indispensable role in dealing with linked or associated loci. In silico analysis can also differentiate subtle consequences of coding DNA variants and remains the major method to predict functionality for non-coding DNA variants, particularly those in promoter regions.