Research on autism and mental disorders has been unsuccessful over the past few decades, as can be inferred from the poor results related to advances in other diseases. It is concerning that, after more than a half century of research based on the Diagnostic and Statistical Manual of Mental Disorders (DSM), no biological markers have been found to prove the validity of the DSM mental disorders. Criticisms to DSM have been focused mainly on the categorical conceptualization, false comorbidity and the polythetic nature of diagnostic criteria. The lack of validity of the DSM model requests for a change in research designs, in order to overcome the problems derived from a paradigm that has stopped to be productive. In the field of clinical practice, it is even more pressing a change of mindset in order to incorporate the heterogeneity of endophenotypes that overflows the classification of the DSM, to adopt a dimensional perspective of mental problems and to develop an alternative interpretation for comorbidity. Related to research are suggested designs based on Domain Research Criteria and a multifactorial analysis with very large samples (big data). For clinical practice it is suggested a dimensional approach based on the specificities of each person with autism.