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Drug-facilitated sexual assault (DFSA) is a complex and ever-prevalent problem presenting to emergency departments. Emergency personnel should consider DFSA in patients who are amnestic to the specific details of the event following a reported sexual assault. The presence of ethanol or a positive routine drug screen in a sexual assault victim does not exclude the potential of a surreptitious drug being present. In addition, a negative routine drug screen does not exclude all potential agents that are used in DFSA. This article discusses agents reported in DFSA. It is imperative for emergency personnel to clearly document the history and the presenting signs and symptoms to assist laboratory personnel to hone in and detect the correct agent used in a DFSA.