The inherent imprecision of behavioral phenotyping is the single most important factor contributing to the failure to discover the biological factors that are involved in psychiatric and neurodevelopmental disorders (e.g., Bearden & Freimer, 2006). In this review article we argue that in addition to an appreciation of the inherent complexity at the biological level, a rather urgent task facing behavioral scientists involves a reconsideration of the role that clinical syndromes play in psychological theorizing, as well as in research into the biological basis of cognition and personality. Syndrome heterogeneity, cross-syndrome similarities and syndrome comorbidities question the relevance of syndromes to biological research. It is suggested that the search for brain endophenotypes, intermediate between genes and behavior, should be based on cross-syndrome, trait classification. Cohort selection should rest on behavioral homogeneity, enabling, when necessary, syndrome heterogeneity.