The role of the emergency physician is to determine whether the psychiatric presentation is due to a medical or psychiatric etiology in order to decide on an appropriate patient disposition. This differentiation is made more difficult because approximately 50% of these patients have concomitant medical illnesses, most frequently hypertension, diabetes, asthma, and substance use disorder. Some psychiatric patients need treatment for agitation prior to evaluation in order to obtain vital signs, pulse oxygenation, and glucose assessment. The evaluation process includes a detailed medical and psychiatric history, medication history, social history, and a physical examination, including a thorough neurologic and mental status evaluation. The “red flags” for medical illness include initial presentation over the age of 45, abnormal vital signs, focal neurologic deficit, exposure to drugs or toxins, abnormal physical exam findings, and cognitive deficit. Some of the elements of the mental status examination are routinely assessed as part of the history and physical exam: appearance, behavior and attitude, and mood and affect. A number of items need to be specifically tested such as disorders of thought inquiring about suicidal and homicidal ideation, insight and judgment about their illness, disorders of perception such as hallucinations, and cognitive impairment using the Mini Mental State Exam or the clock drawing test. Factors associated with high risk of suicide include male gender, unmarried or recent loss of relationship, family history of suicide, substance abuse, history of depression or psychosis, hopelessness, frequent and pervasive thoughts of suicide, previous attempts, availability of a lethal method, and poor social support. Laboratory testing and imaging of psychiatric patients should be clinically driven rather than rote. Patients with new onset of psychiatric symptoms and patients with chronic mental illness and a new psychiatric presentation need such testing. The testing may include complete blood count, serum electrolytes, liver function tests, urinalysis, urine drug screen, alcohol levels, and head CT scan. Elderly patients may need thyroid function testing, ECG, and CXR. Medical illnesses that may masquerade as psychiatric illness include hypoglycemia, hyperthyroidism, and delirium. Delirium has a high rate of mortality and is frequently missed in the ED. It has a fluctuating course with change in consciousness and alertness as well as confusion. Tests of delirium such as the Confusion Assessment Method may be useful to identify these patients.