Hemispheric asymmetries are a basic organizational principle of the human brain and are ubiquitous in the healthy population. Several psychological and developmental disorders have been associated with atypical lateralization patterns, especially with a reduction of asymmetry. Among these disorders are major depressive disorder (MDD), schizophrenia, and autism spectrum disorders, which also show altered stress reactivity and elevated basal levels of the stress hormone cortisol. Recent research, however, has called the importance of altered asymmetries in these disorders into question. Especially for MDD, recent large-scale studies investigating altered asymmetries have not found any association. In this article, we propose that there is an association between altered asymmetry and depression but only for a subset of MDD patients. We present a theoretical framework in which we suggest that different symptom clusters expressed in mental and neurodevelopmental disorders could be associated with different neurostructural and –functional alterations, of which only few display altered asymmetry. Further, we propose that the development of a certain symptom cluster depends on the patient-specific etiology of the disorder and that a strong common factor in the development of the subtype with altered asymmetry across disorders is a chronically altered stress level as well as early life stress. To gather empirical evidence for this speculative theory, future research should focus on assessing and categorizing the etiology of disorders and different types of laterality changes on an individual patient level. Identifying different clinical subtypes and their different treatment prognosis would give rise to the possibility of sub-type-specific treatment plans and ultimately benefit patients.