Citrullus colocynthis Schrad. is an annual plant that grows in the south, center, and east areas of Iran. It is recognized by different pharmacologic activities in traditional Iranian medicine (TIM) (i.e., purgative, anti-inflammatory, antidiabetic, analgesic, hair growth-promoting, abortifacient, and antiepileptic. Some of these activities were confirmed in modern phytotherapy. Adverse events such as colic, diarrhea, hematochezia, nephrosis, and vomiting and narrow therapeutic index cause herbalists to use this plant cautiously. If some points about this plant in TIM are considered, it may be possible to produce more tolerable preparations from this plant. In this article, all aspects of this plant in TIM are reviewed; also, the medicinal properties declared for this plant in TIM are compared with those showed in modern phytotherapy. In addition, opinions of TIM and modern phytotherapy about safety and acceptable dosage of this plant are discussed.