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Today, in clinical practice, factors such as signs and symptoms of mental illness and prior treatments and probable side effects of drugs are taken into consideration when clinician decides a proper treatment for a patient. However, psychiatric patients may exhibit interindividual variability in their responses to psychotropic drugs. Nevertheless, it takes longer duration for diagnose or make differential diagnosis of an illness since some disorders may exhibit similar symptoms. Thus, this variability affects response duration, compliance, effective and toxic levels of drugs and even may cause unresponsiveness. A longer duration for a drug to reduce symptoms or resistance to treatment may lead to poor life quality, disabilities, morbidity and mortality. Moreover, poor response to one treatment does not mean poor response to others. In general, fifty percent of psychiatric patients exhibit, somehow, resistance to treatment. Personal and environmental factors such as stress, smoking, feeding, ethnic background, genetic history and patients’ genome inşuence treatment response. Recently, research has focused on searching predictive factors, endophenotypes and biomarkers to help true diagnosis and to find a more effective treatment with less or no adverse effects. Endophenotypes are markers of an illness, which should not depend on clinical appearance symptoms that should be defined as a trait marker. Biomarkers are measurable characteristics that evaluate normal and pathogenic process, or response to treatment and may be a state or trait marker. For example, negative mood and anhedonia are endophenotypes for major depression, brain derived neurotrophic factors and oxytocin may be biomarkers for bipolar disorder, cognitive deficits such as verbal memory recall, executive functioning are endophenotypes for schizophrenia. In recent years, significant advances have been made in the genetics of mental disorders. Genetic factors are target for personalized medicine to predict drug response and side effects. Most common psychotropics are substrates for CYP2D6, an enzyme, which belongs to cytochrome P450 enzyme family, to be considered as a biomarker. Because the genes coding cytochrome P450 enzymes are highly polymorphic, they lead to differential metabolism of psychotropics. The enzymes metabolic rates play a significant role in the efficacy and side effects of a psychotic drug. Therefore, ultra-rapid metabolizers may need high doses of substrates to be effective in treatment while poor metabolizers exhibit side effects even within normal dose ranges. Genome-wide association studies (GWAS) have showed the relation between Single Nucleotide Polymorphisms SNPs) and common psychiatric disorders such as schizophrenia, major depression, bipolar disorder. There also may be an association between efficacy and side effects of psychotropics and SNPs. For instance, a GWAS identified an association between one single locus at rs17390445 (on chromosome4p15) and relief of positive symptoms with ziprasidone treatment. In conclusion, the studies showed that inter-individual differences determined clinical response and side effects of a psychotropic agent. In the near future, it seems that genetic markers will be promising tools for personalized treatment.