Paradoxical reactions to benzodiazepines have been thoroughly reported since the introduction of this type of drug. The mechanism of benzodiazepine action is through the gamma-aminobutyric acid receptors. Properties of benzodiazepine include sedation, anxiolysis, amnesia, anticonvulsion, and muscle relaxation. Unfortunately, adverse paradoxical reactions can be stimulated by benzodiazepines and are difficult to predict and diagnose. Two cases of paradoxical reactions associated with the use of intravenous midazolam are presented, and the management of this complication and its different etiologies are reviewed. The relationship of the paradoxical reaction to alteration of the cholinergic homeostasis, serotonin levels, the role of genetics, and gamma-aminobutyric acid receptor configuration is discussed.