Aggression is a major clinical problem that spans multiple medical and psychiatric diagnoses. The etiology of aggression is complex, comprising social, psychological, and biological factors. Treatment of aggression is equally heterogeneous with structural (environmental), behavioral, and pharmacologic approaches. Among medications, mood stabilizers and antipsychotics are usually considered first line. Antidepressants are frequently recommended but their anti-aggression effect is limited. Within the available limited data, clozapine stands out as more effective than other antipsychotic medications. One of the prominent differences between clozapine and less effective medications is that the affinity of the compound to the dopamine D4 receptor is quite high and significantly greater than to the D2 receptor (defined as a ratio that is >1). Medications that inhibit both receptors equally, e.g., haloperidol, have anti-aggression properties that are less than seen with clozapine. A specific variant of the D4 receptor with an expansion of the third cytoplasmic loop, which interacts with the G protein second messenger system, has been implicated in the etiology of aggression. The proposal is put forward that blockade of the D4 receptor, without concomitant significant blockade of D2, increases the anti-aggression effect of the medication. This hypothesis can be tested using a new antipsychotic, asenapine, which is the only other antipsychotic with antagonistic affinity ratio of D4/D2>1.