Although a very useful guideline for orally bioavailable small-molecule drug design, the 'rule-of-five' (also known as 'Lipinski's rule of drug-likeness') has to some extent been overemphasized. Firstly, only 51% of all FDA-approved small-molecule drugs are both used orally and comply with the 'rule-of-five'. This does not even include the increasing number of biologicals of which several have reached 'blockbuster' status. Secondly, it does not cover natural product and semisynthetic natural product drugs, which constitute over one-third of all marketed small-molecule drugs. A more balanced and programmatic approach to drug discovery should be more productive than to rely on an overemphasis of 'rule-of-five' compliance. Rather it should consider proactively the development of parenteral drugs in parallel to oral drugs and to consider the development of therapeutic antibodies in parallel to small-molecule drugs. These are particularly relevant for efforts against 'first-in-class' and/or particularly challenging targets such as proteases and those involving protein-protein interactions. In addition, more effort should be invested in natural product research. Emerging novel technologies such as synthetic biology (genetic engineering of living organisms to produce small-molecule therapeutics) may address several challenging issues of natural product-based drug discovery including synthetic feasibility and ligand efficiency.