This chapter reviews how functions of genetic susceptibility factors can be validated, specifically using disrupted in schizophrenia 1 (DISC1) as an example. Studies at multiple levels, from protein chemistry, cell biology, animal study, to clinical work provide comprehensive understanding of the functions of susceptibility factors. Once genetic studies identify candidate susceptibility factors for the diseases, functions of such proteins can be tested in cells by modulating expression of the target molecules or by expressing their genetic variants. The chapter describes rodent models with manipulations for genetic susceptibility factors of mental illnesses in greater detail. A series of studies by Weinberger and associates has pioneered the possible correlation of brain dysfunction with genetic variations in susceptibility factors associated with mental illnesses. To identify mechanistic links from genetic factors to the phenotypes, especially those observed during brain development and maturation, a combination of human studies with animal experiments is expected.