Atypical antipsychotics are antagonists at serotonin 5-HT2A and dopamine D2 receptors. However, their effects on negative symptoms and cognitive deficits remain modest and they disrupt metabolic function. Recent drugs, such as aripiprazole, perospirone, bifeprunox, lurasidone and cariprazine act as D2 receptor antagonists (or partial agonists) combined with 5-HT1A receptor activation. The latter prevents extrapyramidal symptoms, favors prefrontal cortex dopaminergic neurotransmission, has a beneficial influence on mood and opposes cognitive deficits. Further, recent drugs exhibit little interaction at sites associated with side-effects such as metabolic disorders or autonomic disturbance. However, these drugs differ in their balance of 5-HT1A/D2 receptor properties and this is likely to translate to distinct therapeutic profiles.