Ever since clozapine was discovered, researchers have been attempted to answer the question of what makes it different and how to relate its many pharmacological actions to its clinical features. Its clinical profile conflicts with the hypothesis that antipsychotic effect is due entirely to D2 dopamine receptor blockade. Clozapine is known to interact with many neurotransmitters systems. To date, four main hypothesis have been proposed in an attempt to explain some or all for clozapine's atypical properties: selective blockade of mesolimbic dopamine function; D1, D2, D3 and D4 receptor blockade; 5-HT2 and D2 receptor blockade; Potent alpha 1 adrenergic blockade. These hypothesis are reviewed in relation to the clozapine clinical profile. No hypothesis fully accounts for clozapine's spectrum of neurotransmitter interactions. Such a multiplicity of action would preclude a unified mechanism.