Autism spectrum disorders (ASD) are a class of neurodevelopmental disorders, which affect 1 out of 110 children. Children and adolescents diagnosed with ASD often suffer from severe irritability, including aggression, self-injurious behavior, and tantrums (about 68% of patients). Managing irritability with an effective and safer agent can improve overall functioning in individuals with autism and alleviate burdens on the individual and family. Research into the pharmacotherapy of severe behavioral disturbance in ASD has primarily focused on the atypical antipsychotics. The Food and Drug Administration (FDA) approved risperidone and aripiprazole for the treatment of irritability associated with ASD. Risperidone was approved by FDA in 2006 for the children and adolescents of age 5 to 16, with a maximum recommended dose of 3 mg/d. Aripiprazole was approved by FDA in 2009 for the patients of age 6 to 17. The usual recommended clinical dose for maintenance is between 5 and 15 mg/d. Clozapine, olanzapine, quetiapine, ziprasidone, paliperidone are other atypical antipsychotics which are used for irritability in children and adolescents with ASD. Relatively small sized controlled studies of the anticonvulsants and mood stabilizers (lithium, divalproex sodium, lamotrigine, levetiracetam) for irritability in youth with ASD have generally demonstrated negative results. Alpha2 adrenergic agonists such as guanfacine may be useful for milder irritability symptoms in ASD. One recent study investigated use of the glutamatergic modulator and antioxidant N-acetylcysteine (NAC) for irritability in ASD. In this double blind, placebo-controlled trial, subjects in the NAC group, compared to the placebo group, demonstrated significant improvement in irritability as measured. Additional research is needed to understand the potential role of alpha2 adrenergic agonists and NAC better, as in the treatment of irritability in ASD.