Genetic 16p11.2 and 22q11.2 deletions and duplications in humans may alter behavioral developmental trajectories increasing the risk of autism and schizophrenia spectrum disorders, and of attention‐deficit/hyperactivity disorder. In this review, we will concentrate on 16p11.2 and 22q11.2 deletions' effects on social functioning, beyond diagnostic categorization. We highlight diagnostic and social sub‐constructs discrepancies. Notably, we contrast evidence from human studies with social profiling performed in several mouse models mimicking 16p11.2 and 22q11.2 deletion syndromes. Given the complexity of social behavior, there is a need to assess distinct social processes. This will be important to better understand the biology underlying such genetic‐dependent dysfunctions, as well as to give perspective on how therapeutic strategies can be improved. Bridges and divergent points between human and mouse studies are highlighted. Overall, we give challenges and future perspectives to sort the genetics of social heterogeneity.