Commonly used medications can have neuropsychiatric and behavioral effects that may be idiosyncratic or metabolic in nature, or a function of interactions with other drugs, toxicity, or withdrawal. This article explores an approach to the patient with central nervous system toxicity, depending on presentation of sedation versus agitation and accompanying physical signs and symptoms. The effects of antihypertensives, opioids, antibiotics, antiepileptic agents, steroids, Parkinson’s disease medications, antipsychotics, medications for human immunodeficiency virus infection, cancer chemotherapeutics, and immunotherapies are discussed. A look at the prevalence of adverse reactions to medications and the errors underlying such occurrences is included.