Recent case reports in medical literatures suggest that more and more second-generation atypical antipsychotics (AAs) have been prescribed for off-label use; quetiapine (Brand name: Seroquel®) showed increase in its trend for off-label use. Little is known about the reasons behind this trend, although historical sedative and hypnotic prescription patterns suggest that despite relatively superior safety profiles of quetiapine (especially for movement disorders), it may be used for treating substance abuse disorder. In addition, recent studies have shown a strong potential for misuse and abuse (MUA) of quetiapine beyond Food and Drug Administration-approved indications. This includes drug-seeking behaviors, such as feigning symptoms, motivated by quetiapine and use of quetiapine in conjunction with alcohol. Quetiapine appears to be the most documented AA with street values bartered illicitly on the street. A recent report from the Drug Abuse Warning Network has shown a high prevalence of quetiapine-related emergency department visits involving MUA. Several other case studies have found that quetiapine causes seeking behaviors observed in substance use disorder. In fact, the majority of quetiapine MUA involved patients diagnosed with substance use disorder. In the absence of a definitive mechanism of action of quetiapine's reinforcing properties, it is imperative to gather robust evidence to support or refute increasing off-label use of AAs.