The use of herbal medicines (HM) is on the rise among the global population. Although the safety profile of many herbal medicines is promising, accumulated data show evidence of significant interactions with medications, which can place individual patients at great risk. A range of electronic databases have been reviewed for articles published in this field: Medline, Allied and Complementary Medicine Database, HealthSTAR, AMBASE, CINHAL, Cochrane Library, as well as Internet documents and manually searched references in medical journals. In this review, we examined the literature from 1966 to 2006 and focused on the importance of the risk of drug interactions and potential side effects when HM are involved. We discuss these in light of the documented findings. A review of the problematic issues is given and recommendations are made in order to encourage the setting up of clinical trials on HM and herb-drug interactions.