We reviewed what should be learned from schizophrenia to develop specific intervention for 22q11.2DS. In our opinion, the first step of CBT approach in 22q11.2DS with psychotic symptoms is to identify precisely which tools can be used among the already available ones. Cognitive behavioral therapy (CBT) targets integrated disorders, i.e. reasoning biases and behavior disorders. In 22q11.2DS, CBT-targeted behavior disorders may take the form of social avoidance and withdrawal or, in the contrary, a more unusual disinhibition and aggressiveness. In our experience, other negative symptoms observed in 22q11.2DS, such as motivation deficit or anhedonia, may also be reduced by CBT. Controlled trials have been studying the benefits of CBT in schizophrenia and several meta-analyses proved its effectiveness. Therefore, it is legitimate to propose this tool in 22q11.2DS, considering symptoms similarities. Overall, CBT is the most effective psychosocial intervention on psychotic symptoms and remains a relevant complement to pharmacological treatments such as antipsychotics.