The comprehensive drug screen has serious limitations when used as the sole study for diagnosing intoxication. A careful history and physical examination in the poisoned patient can provide important clues that point to possible toxins. Ancillary studies help differentiate the most likely poison and guide treatment. Fortunately, most poison victims do well with supportive care alone. However, the clinician should be aware of agents that can cause significant harm to patients if not detected and treated quickly. Iron and carbon monoxide are good examples of lethal agents that need a high index of clinical suspicion for early recognition and require specific therapy to ensure a good outcome. Patients who overdose with clonidine, calcium-channel blockers, beta-adrenergic blockers, or albuterol must be managed expectantly and according to their clinical presentation because rapid laboratory verification is not available for these poisons. In all situations, the clinician must integrate information from history, physical examination, and laboratory to render the best care.