Since the late 1990s, novel insights into molecular biology and carcinogenesis enabled the rational design of mechanism-based anticancer therapeutics. The large number of natural product (NP)-derived drugs currently under clinical evaluation and the recent approval of temsirolimus (Torisel®) as a first mTOR protein kinase inhibitor indicate that NPs have to be considered not only as a seminal source of cytotoxic, but also as a source of molecularly targeted agents. Whereas molecular modeling is well established as an important and successful method to discover and rationalize bioactivities in medicinal chemistry research, its application has proven to be also a powerful tool in the field of NPs. This review highlights the impact of computer-assisted approaches on NPs as molecularly targeted anticancer drugs. Examples of applications are provided focusing on innovative targets such as protein kinases, tumour vasculature, epigenetic modulators, heat shock protein (Hsp) 90, and direct apoptosis enhancers.