During the last decades a large number of cucurbitacins have been isolated from various plant species belonging to other plant families than Cucurbitaceae. Although the roots and the fruits of plant belong to these Cucurbitaceae species are very bitter, they have been used as folk medicines in some countries because of their wide spectrum of pharmacological activities such as anti-inflammation and anticancer effects. In the last ten years, cucurbitacins had been shown to inhibit proliferation and induced apoptosis utilizing a long array of in vitro and in vivo cancer cell models. Several molecular targets for cucurbitacins have been discovered, such as fibrous-actin, signal transducer and activator of transcription (STAT), cyclooxygenase-2, etc. This review aimed at elucidating the natural sources of some cucurbitacin compounds, their chemical structure and derivatives, physical properties, biological activities and mechanism by which they reduce the proliferation human cancer cells. This widens our armaments against a devastating disease that we are failing to face.