Antipsychotic-induced extrapyramidal side effects have a negative impact on treatment for mental illness. Acute dystonic reactions are uncomfortable and frightening to the patient, and often lead to early discontinuation of drug therapy and worsened long-term outcome. The lower propensity of the atypical antipsychotic agents to cause extrapyramidal symptoms (EPS) has been associated with multiple benefits, including improved adherence. The authors describe a 57-year-old male patient who was in the treatment refractory unit. This patient exhibited extreme sensitivity to antipsychotic agents, experiencing acute dystonic reactions with quetiapine and olanzapine, in addition to older typical antipsychotic agents. The patient has not experienced acute EPS since therapy with aripiprazole was initiated. Further complicating this patient's course is his unusual sensitivity to experiencing dystonic reactions. We have observed acute dystonias in the absence of antipsychotic treatment and in the context of seizure activity (or paroxysmal dyskinetic activity). The true etiology of the latter dystonic activity has not been completely determined due to the patient's unwillingness to cooperate with invasive testing. None of the gene variations tested (CYP2D6 phenotype, two dopamine D2 receptor variants and one D3 receptor variant) appeared to explain the patient's vulnerability to acute dystonic reactions.