Despite extensive research, our knowledge of structural or functional pathology of severe mental disorders such as schizophrenia and major affective disorders is limited. The only etiological factor with reasonably firm foundation is inheritance, as evidenced by family, twin and adoption studies, however, the molecular basis of this heritability is not established yet. In the absence of clear knowledge about the biological substrate for these psychiatric disorders all the genes expressed in the human brain are potential candidate genes. Association studies analyze genetic variants (polymorphisms) in genes with presumed functional significance in the pathophysiology of the disease (candidate genes). These genetic studies compare the frequency of the hypothetical risk variant in people affected by the disease and in healthy control representatives of the same population. Also, simplex families with an affected child (trios) or with discordant affected offspring (quadruplets), can be used in the association studies. This strategy constitutes a tool to identify the small and moderate effects of genes in these complex phenotypes. Likewise, these kinds of studies could be useful to explain the effect of genes in some specific traits and symptoms present in functional psychoses. Some of our own results on serotoninergic system genes and major depression are included in this chapter as an example of case-control association developed studies in mental disorders.