This article reviews the off-label prescription of quetiapine in the treatment of a broad range of psychiatric disorders including obsessive–compulsive disorder, post-traumatic stress disorder, personality disorder, substance abuse, bipolar disorder (now US FDA approved), anxiety and depression. The article highlights the primary reliance on selective serotonin reuptake inhibitors (SSRIs) in the treatment of these disorders (cf bipolar disorder) and the high percentage of patients (30–60%) that do not respond to SSRIs. The studies suggest that low-dose quetiapine shows good tolerability and efficacy in patients diagnosed with these disorders, particularly in the case of treatment-resistant patients that do not respond to primary treatments including SSRIs and cognitive–behavioral therapy. Quetiapine generally appears to be very effective in trauma-related conditions by improving autonomic stability, and decreasing the stress and anxiety response that arises due to specific fears or triggers. Quetiapine also appears to be particularly useful for normalizing obsessions and compulsions, and improving low mood, irritability and aggressiveness. A greater understanding of the pharmacology of drug alternatives and the neurobiology of psychiatric disorders is required to permit a more personalized medicine approach.