Cancer is a major health concern and leading burden on economy worldwide. An increasing effort is devoted to isolation and development of plant-derived dietary components as effective chemo-preventive products. Phytochemical compounds from natural resources such as fruits and vegetables are responsible for decreasing the risk of certain cancers among the consuming populations. Apigenin, a flavonoid phytochemical found in many kinds of fruits and vegetables, has been shown to exert significant biological effects, such as anti-oxidant, anti-inflammatory and most particularly anti-neoplastic properties. This review is intended to summarize the most recent advances in the anti-proliferative and chemo-preventive effects of apigenin in different cancer models. Analysis of the data from the studied cancer models has revealed that apigenin exerts its anti-proliferative effects through multiple and complex pathways. This guided us to discover some controversial results about the exact role of certain molecular pathways such as autophagy in the anticancer effects of apigenin. Further, there were cumulative positive evidences supporting the involvement of certain pathways such as apoptosis, ROS and DNA damage and repair. Apigenin possesses a high potential to be used as a chemosensitizing agent through the up-regulation of DR5 pathway. According to these preclinical findings we recommend that further robust unbiased studies should consider the possible interactions between different molecular pathways.